599
Development
The decade of the developing brain
Thomas M Jessell* and Joshua R Sanes†
Our understanding of neural development has advanced
dramatically over the past decade. Significant insights have
now been obtained into seven fundamental developmental
processes: first, induction of the neural plate; second,
regionalization of the neural tube along the dorsoventral and
anteroposterior axes; third, generation of neurons and glia from
multipotential precursors; fourth, apoptotic cell death; fifth,
migration of neurons; sixth, guidance of axons to their targets;
and seventh, formation of synapses.
Addresses
*Department of Biochemistry and Molecular Biophysics, Howard
Hughes Medical Institute, Columbia University, 701 West 168th Street,
New York, NY 10032, USA; e-mail: tmj1@columbia.edu
† Department of Anatomy and Neurobiology, Washington University
School of Medicine, 660 South Euclid Avenue, St Louis, MO 63110,
USA; e-mail: sanesj@pcg.wustl.edu
Current Opinion in Neurobiology 2000, 10:599–611
0959-4388/00/$ — see front matter
© 2000 Elsevier Science Ltd. All rights reserved.
Abbreviations
bHLH basic helix-loop-helix
BMP bone morphogenetic protein
FGF fibroblast growth factor
LDL low-density lipoprotein
NGF nerve growth factor
TGF transforming growth factor
Introduction
We have not yet read the other reviews in this special
anniversary issue, but it is a safe bet that most of them
point to the unprecedented pace of discovery during the
past decade. Here, we make the same claim for studies of
neural development. Indeed, perhaps because develop-
mental neurobiology was still an immature field a decade
ago, it may be that its progress is even more striking than
that of some other areas of neuroscience. Yet, the rising
tide of progress has not lifted all developing boats to an
equal extent. Indeed, as we try to explain below, the
developmental neurobiologists’ view of progress should
vary in rosiness in accord with the stage of development
under examination.
In this brief review, we first outline why one might be
interested in the field’s progress. Then, rather than focus-
ing on specific experiments or discoveries, we pinpoint
seven areas that we, as well as many colleagues canvassed
for their views in the course of preparing this review,
believe have advanced in impressive ways over the past
decade. We finish with some general comments on the rea-
sons for this rapid progress and on the clinical implications
of the new findings. Throughout, we try to take note of the
many challenges that remain.
Why study neural development?
Some view the early development of the nervous system as
a suitable arena for addressing fundamental issues in devel-
opmental biology because, although not especially tractable,
it is especially interesting. If it is almost as easy to under-
stand the differentiation of a neuron as a keratinocyte, why
not choose the neuron? Others take the view that under-
standing how the diversity of neuronal cell types is
generated may provide some insights into a later and more
distinctive aspect of neural development, the formation of
neuronal circuits. That is, as one moves downstream from
the transcriptional regulators that specify cell fate, it may be
possible to define sets of effector molecules — intercellular
signals or intracellular signaling factors — that control con-
nectivity. It is even possible that aspects of the logic of these
later developmental steps will emerge from earlier decisions
about neuronal subtype identity.
Regardless of individual motivation, for students of these
early stage of neural development — the ones in which
neurons most resemble other cells types — progress has been
remarkable, and key steps are understood at a much more
profound level now than they were a decade ago. Moreover,
studies of processes such as neural induction, neurogenesis,
and neuronal survival have provided us with core biochemi-
cal programs of great explanatory power. Even though many
fundamental questions remain unanswered, clear strategies
have emerged for addressing them, and many tools with
which to achieve further progress are now available.
Another group of neurobiologists is most interested in the
later developmental steps that make the brain unique
among organs. These steps include the migration of neu-
rons to appropriate nuclei and laminae, the growth of axons
towards their targets, the elaboration of dendritic arbors,
and the formation of synapses. Together, these phenomena
account for the most remarkable physical feature of the ner-
vous system, the specificity with which its component cells
interconnect. In these middle stages, progress has been
striking, albeit not overwhelming. Core programs with a
consistent logic continue to prove elusive; indeed, it is not
yet clear whether they exist. But, in marked contrast to the
situation in 1990, we now know the names of many key
molecules and are, therefore, in a favorable position to ask
critical questions about how these processes are controlled.
For a third group of neurobiologists, those interested in
still later events such as the development of behavior, the
situation is less secure. We still understand little about the
assembly of any neural circuit that controls a defined
behavior. But there is solace in the thought that some of
the advances in the mechanisms of axonal growth and
600 A decade of Current neurobiology
Figure 1
A molecular pathway for neural induction
Ectodermal Default Neural
cell cell
BMP BMP
RNA protein
Chordin
FGFs Noggin
(pre-gastrula)
Other BMP inhibitors
Organizer
(node)
Gastrula
Current Opinion in Neurobiology
A molecular pathway for neural induction in the vertebrate embryo.
Model of signaling pathways currently thought to regulate the
tranformation of ectodermal cells into neural cells. In the absence of
any extrinsic signals, ectodermal cells would acquire a neural fate by
‘default’. However, this neural differentiation is normally prevented by
tonic BMP signaling between ectodermal cells. Prior to gastrulation,
FGF signaling promotes neural differentiation by repressing the
expression of BMP genes from prospective neural regions of the
ectoderm. During gastrulation, antagonists of BMP protein activity
such as noggin and chordin are secreted by the Organizer (node)
region and ensure the progression of neural differentiation. For further
details, see text.
synaptic connectivity should begin to have an impact on
the development of behavior in the coming years.
Finally, some neurobiologists are motivated by a desire to
understand the origin of neurological and psychiatric diseases
and to use this information to effect cures. For this group,
development is a newfound passion, fueled by the deepen-
ing conviction that many such maladies, including some of
the most poorly understood, result from aberrant develop-
mental programs. A decade ago, such a clinically directed
endeavor seemed — and, in fact, was — hopeless, but now is
an area of considerable, if as yet unfulfilled, promise.
Making neurons: from experimental
embryology to core programs
Neural induction [1–3]
A fundamental early step in neural development, at least
in vertebrates, is the allocation of a group of ectodermal
cells as precursors of the entire nervous system. This
process involves an inductive interaction first appreciated
by Spemann and Mangold in the 1920s. Their experiments
focused attention on the signaling properties of a group of
embryonic cells that they called the organizer. For much of
the past century, the identification of the organizer’s neural
inducing signals was viewed as arguably the most
important task for students of early neural development.
Progress in understanding vertebrate neural induction can
be subdivided into three phases, which precede, span and
conclude the decade of the 1990s around which this review
is focused. Prior to 1990, the molecular nature of neural
inducing factors remained obscure and biochemical
attempts to isolate such factors failed. With hindsight,
these pioneering attempts can be viewed as premature,
because the assay systems used to monitor neural differen-
tiation and the biochemical tools used to purify relevant
factors were too primitive.
During the early 1990s, this situation changed radically
with the introduction both of definitive neural markers that
could be used to report the state of neural differentiation
and of expression cloning methods that finessed the need
for protein purification. Once these advances were in place,
many candidate neural inducing factors emerged — nog-
gin, follistatin, chordin, Xnr3 and their relatives — largely
from functionally based expression screens in Xenopus
embryos. As more and more inducers were discovered, it
became clear that they shared the ability to inhibit signals
transmitted by members of a family of secreted factors pre-
viously implicated in skeletal development, the bone
morphogenetic proteins (BMPs). In parallel, in vitro assays
began to indicate that undifferentiated ectodermal cells
could acquire neural markers on their own, in the absence
of any of the putative inducers. Together, these data sug-
gested a model of neural induction in which ectodermal
cells are fated to give rise to epidermal derivatives unless
ongoing BMP signaling within the ectoderm is inhibited by
factors derived from the organizer region (Figure 1).
Although the BMP-inhibitor model was attractive in its
simplicity, several apparently inconsistent results surfaced
near the end of the 1990s. Mouse mutants lacking genes
encoding candidate neural inducers expressed by the orga-
nizer region (the node in mouse), still exhibited neural
differentiation. Moreover, genetic elimination of the
mouse node in its entirety similarly failed to block neural
differentiation. How can these findings be reconciled with
the simple mid-1990s version of events? It now appears
that neural induction begins prior to the formation of the
organizer region and thus must be initiated by signals
derived from other cell types. In addition, members of
other families of signaling molecules, notably the fibrob-
last growth factors (FGFs) have now been proposed as
early-acting factors that initiate neural induction. So the
suppression of BMP signaling may maintain rather than
initiate the process of neural differentiation.
On the other hand, these new findings may, in the long run,
serve to expand rather than overturn the BMP-inhibition

hypothesis. FGFs have been shown to function, at least in
part, by repressing the expression of BMP genes at a tran-
scriptional level, in contrast to the organizer-derived factors
such as noggin and chordin, which act extracellularly to
block BMP activity. Thus, the new data are not inconsistent
with the idea that suppression of BMP signaling, by hook or
by crook, lies at the heart of neural induction (Figure 1).
In retrospect then, we began the 1990s knowing nearly
nothing about the cellular or molecular bases of neural
induction, passed through a brief period when the process
appeared to be simple and straightforward, and leave the
decade with a richer, more complex, and hopefully more
realistic view. That is, we now appreciate neural induction
as a multistep process, with distinct signaling factor
requirements at successive steps. Although current views
remain somewhat fragmentary, we expect they will soon
blend into a more harmonious account of this fundamental
aspect of neural development.
Regionalization of the neural tube [1,4–6]
In the 1940s and 1950s, experimental embryological studies
by Roach, Jacobson and others provided evidence that cells
in the neural tube acquire their regional identity by virtue
of the position that they occupy along two primary neural
axes: dorsoventral and anteroposterior. Inherent in this
model was the idea that the position of a cell defines its
identity through exposure to regionally restricted signaling
factors that operate over these two neural axes. This idea
provided a fundamental framework for many subsequent
studies of regional neural patterning. Unfortunately, techni-
cal limitations similar to those described above for neural
induction slowed progress over the ensuing three decades,
so this framework remained skeletal and lacked validation.
During the 1990s, however, many neural patterning factors
were identified. Moreover, it has been possible to pinpoint
the cellular source of many of these factors, and promising
first steps have been taken in elucidating the intracellular
signaling pathways through which they act.
With these advances, neural cell groups that previously
represented anatomical curiosities of obscure nomencla-
ture and function — the floor plate, the roof plate, the
isthmus and the zona limitans intrathalamica, to name but
four — have come to be appreciated as key sources of
secreted factors that establish regional pattern. In addition,
it has become apparent that a relatively small number of
signaling factor families — notably, TGF-βs (including
BMPs), hedgehogs, FGFs, Wnts and retinoids — can
account for many features of regional cell specialization
within the neural tube. Along the dorsoventral axis, the
two primary signaling factors appear to belong to the
hedgehog and BMP families. A useful oversimplification is
that the hedgehogs mark the ventral and BMPs the dorsal
limit of the axis (Figure 2a). Along the anteroposterior axis,
the situation is somewhat more complex, with retinoids,
FGFs, hedgehogs, Wnts and BMPs all proposed to func-
tion in different locations or developmental windows
Development Jessell and Sanes 601
(Figure 2b). In some instances, the combinatorial actions
of several factors acting on a single region or cell appear to
establish regional pattern and neuronal diversity. In other
cases, inductive factors, most notably Sonic hedgehog, can
act as gradient signals, or morphogens — inducing distinct
neuronal subtypes at different concentration thresholds.
In parallel with the definition of extrinsic signaling mole-
cules, advances in the biochemical characterization of
transcriptional regulatory mechanisms in mammalian
cells, combined with the molecular cloning of genes
responsible for homeotic transformations of body parts in
Drosophila melanogaster in the late 1980s, propelled
sequence-specific DNA-binding proteins — loosely, tran-
scription factors — into the forefront of studies on cell
fate determination in the nervous system. Current esti-
mates, admittedly still subject to wild fluctuation, indicate
that there are thousands of transcription factors in the
mammalian genome. The little we know about the subset
of these factors that are expressed in the developing
nervous system indicates that different categories of tran-
scriptional regulators, many containing homeodomains,
play pivotal roles at several successive steps in neural
induction (e.g. Sox genes), regional patterning (e.g. Pax
and Nkx genes; see Figure 2a), and cell fate determina-
tion (e.g. LIM and POU genes). The sheer number of
transcription factors recognized to exhibit cell-type-
specific patterns of expression in the nervous system has
posed the additional question of whether some of them
act in a dedicated manner to direct specific cell fates.
As a result of the deluge of recent information about sig-
nals and transcriptional regulators, there is now quite a bit
of flesh on the bones of the model outlined by Roach and
Jacobson. Moreover, there are clear and testable ideas
about how to solve a major remaining problem: linking
extrinsic signals to the nuclear events that define cell-spe-
cific patterns of gene expression. Nonetheless, a critical
‘systems-level’ question remains largely unresolved: how
are dorsoventral and anteroposterior patterning mecha-
nisms integrated within individual cells to specify their
unique identities?
Neurogenesis [7–10]
By 1990, descriptive studies of neuronal lineages had pro-
vided evidence that the developmental potential of neural
progenitors is restricted progressively with time and
advancing cell division, and that cells become committed to
particular fates only late in their developmental history.
Related studies had also raised the possibility that the deci-
sion of a newborn cell to become either a new progenitor or
a neuron is related to the way in which the progenitor
divides. One influential suggestion was that symmetrical
divisions of stem cells generate more stem cells whereas
asymmetrical divisions give rise to differentiated progeny.
However, there was no understanding of the mechanisms
that regulate the mode of mitosis or govern the transforma-
tion of an undifferentiated cell into a neuron or glial cell.
602 A decade of Current neurobiology

Figure 2

Inductive signals and regional patterning of the neural tube

(a) Dorsoventral
Roof plate MATH 1

Pax3
Pax7 D1
BMPs
D2

D3

Dbx2
V0
DV V1
boundary Nkx6.1 V2
Shh
V3 MN

Floor plate Nkx2.2

Shh

Notochord

(b) Rostrocaudal M
H
F
SC
Reti
FGF noid
FGF s
Wnt

Isthmus
Shh

Zona
limitans
intrathalamica

Forebrain Midbrain Hindbrain Spinal cord

(F) (M) (H) (SC)
Current Opinion in Neurobiology

Some of the factors proposed to establish regional pattern along the
dorsoventral and rostrocaudal axes of the neural tube. (a) Dorsoventral.
Sonic hedgehog (Shh)-mediated signals from the notochord and floor
plate and BMP-mediated signals from the roof plate initiate the
dorsoventral patterning of the neural tube. The regional differentiation of
neural progenitor cells is marked by the expression of transcription factors
of the homeodomain and bHLH families. The combination of transcription
factors expressed by progenitor cells determines the subtype identity of
dorsal (D) and ventral (V) neuronal subtypes. DV, dorsoventral; MN, motor
neuron. Adapted from [1]. (b) Rostrocaudal. Specialized neural cell
groups arrayed along the rostrocaudal axis of the neural tube, such as the
zona limitans intrathalamica and isthmus, provide a source of secreted
factors that establish regional identity and neuronal fate in adjacent
domains of the neural tube. Cells of the isthmus secrete FGFs and Wnts,
both of which are required for the differentiation and patterning of the
midbrain and hindbrain. Adapted from [1].

Over the past decade, we have obtained such a rich
understanding of these processes that we can begin to
define a core program of neurogenesis. Once again, key
insights into this issue derived from studies in
Drosophila. Here, earlier work had identified a set of
neurogenic genes, the loss of which resulted in the
generation of excess neurons at the expense of support-
ing cells. These studies also led to the idea that the
selection of the neural fate depended on a lateral, inter-
cellular signaling process that operated between
neighbors, directing one to become a neuronal precursor
and the other to acquire a non-neural fate. Molecular
 Development Jessell and Sanes 603

Figure 3

Regulation of neurogenesis by Notch

signaling and bHLH transcription factors. (a) Initially, Notch signaling between cells is balanced
Diagram shows the interplay between Notch Delta Notch
signals and bHLH factor expression during
neurogenesis in Drosophila. A similar series Achaete-
of interactions is thought to control scute
neurogenesis in vertebrates. (a) Notch proteins
signaling between cells is initially similar in
the proneural region of the ectoderm that
expresses bHLH transcription factors of the
achaete-scute class. (b) A slight imbalance
in Notch signaling develops between cells.
One cell begins to express higher levels of
Delta and thus activates Notch to a higher
level in the neighboring cell. (c) The initial Achaete-
imbalance in the level of Notch signaling is scute
amplified by a feedback pathway mediated proteins
by bHLH proteins. Cells in which Notch Notch Delta
signaling is relatively low become neuroblast
precursors, and cells in which Notch
(b) An imbalance in Notch signaling develops
signaling is high become glial/epidermal
cells. Modified from [7].
Achaete- Suppressor
scute of hairless
proteins

Enhancer Enhancer
of split of split
proteins proteins

Achaete-
Suppressor scute
of hairless proteins

(c) The imbalance is quickly amplified, leading to development of a neuronal precursor

Achaete- Suppressor
scute of hairless
proteins

Enhancer
bHLH of split
proteins proteins

Achaete-
scute
proteins

Cell becomes a Cell becomes a

neuronal precursor glial/epidermal cell

Current Opinion in Neurobiology

analysis revealed that key neurogenic genes encoded
components of this signaling pathway, including the
membrane-associated ligands, Delta and Serrate, and
their transmembrane receptor, Notch. Activation of
Notch signaling biases cells towards non-neural fates and
inhibition of Notch signaling promotes neuronal differ-
entiation (Figure 3). Moreover, it has become apparent
that the Notch signaling pathway is highly conserved
and also exerts a pivotal role in the control of neuro-
genesis in vertebrates.
604 A decade of Current neurobiology
The analysis of Notch signaling in Drosophila has also led
to the identification of intracellular proteins that regulate
Notch function. Prominent among these is the Numb pro-
tein. In many cells, Numb appears to bind to Notch and
inhibit Notch signaling, thus promoting neuronal cell fates.
This interaction appears to be a critical part of the elabo-
rate cellular machinery used to endow sibling cells with
distinct fates following asymmetric divisions. Numb and
many other proteins are concentrated at one pole of prolif-
erative neural precursors, and so they are segregated to one
or both daughters, depending on the mitotic plane. As a
consequence, the symmetry (or asymmetry) of a cell divi-
sion may influence the nature of the progeny via
symmetrical (or asymmetrical) intracellular partitioning of
the same Notch pathway components that are activated
extracellularly by neighboring cells. As many of the same
proteins exist in developing vertebrate neural cells, it is
plausible to think that the same mechanisms are at play.
Studies of neurogenesis in Drosophila have also revealed
many of the upstream regulators and downstream effec-
tors of Notch signaling. Most notably, transcription
factors of the basic helix-loop-helix (bHLH) class have
been shown to have central roles in defining groups of
proneural cells — cells that have the capacity to assume
neural fates under the control of Notch signaling.
Members of the same gene families play independent
roles in directing the progression of neuronal differentia-
tion once fate has been determined. Close relatives of
these genes have been identified in vertebrates and
shown to have strikingly similar functions in controlling
the decision of progenitor cells to remain proliferative or
to acquire neuronal or glial fates.
With the definition of this core neurogenic program, it
may now be possible to address crucial mechanistic ques-
tions. For example, the decision of progenitor cells to
express neuronal properties is often tightly linked to the
decision to exit the cell cycle, yet little is known about the
integration of these two programs. Recent evidence sug-
gests that certain neurogenic bHLH proteins can drive
neural precursor cells out of the cell cycle, but it remains
uncertain whether this is a general property of these pro-
teins, and the biochemical basis of the intersection
between bHLH transcription factors and cell cycle
machinery is obscure. In addition, the concept of lateral
signaling as a method of forcing binary cell fate decisions
during neural development implies a high degree of feed-
back control during the period that cells make these
decisions, but as yet few of the proteins that mediate such
feedback interactions have been identified. Thus, despite
many striking advances in understanding basic programs
of neurogenesis in vertebrates, details of the pathway of
neuronal differentiation remain sketchy.
Neuronal survival and apoptosis [7,11–13]
Studies on the control of neuronal survival have an illustri-
ous history in neural development. The pioneering studies
of Levi-Montalcini and Hamburger on naturally occurring
(now called programmed) neuronal cell death culminated
in the characterization and isolation of nerve growth factor
(NGF) in the 1950s. NGF has a place in the developmen-
tal neurobiologists’ pantheon somewhat equivalent to that
of acetylcholine, the first neurotransmitter substance to be
isolated. By the end of the 1980s, the neurotrophic hypoth-
esis was firmly entrenched, and NGF was appreciated to
be the pioneer member of a large and still expanding group
of secreted factors that control whether neurons live or die.
What was lacking was any understanding of what pro-
grammed death, or apoptosis, actually entailed. Lacking
this knowledge, it was impossible to know how neuro-
trophic factors actually controlled survival. Perhaps the
major advance in this area over the past decade has been
the eludication of key mechanisms of apopotosis.
Many of the crucial insights into the biochemical nature of
this cell death program emerged from genetic studies in
the nematode worm Caenorhabditis elegans. The key func-
tions of the Ced genes in controlling cell death in the worm
were shown to be conserved in striking fashion in verte-
brate embryos, revealing the pivotal roles of the Bcl-2,
APAF and caspase families of proteins in the regulation of
cell death. Briefly, the caspases are proteases that serve as
final common agents for suicide within cells. The Bcl-2
pathway is one of several that regulate the activity of the
caspases, holding them in check or promoting their activi-
ty. One major function of neurotrophic factors appears to
be to suppress the apoptotic program (Figure 4), providing
a satisfying link between an initially arcane aspect of
neuroembryology and a phenomenon of fundamental
importance to all multicellular systems.
By the end of the decade, the combination of genetic stud-
ies in worms and flies and of the biochemical dissection of
protein function in vertebrates has resulted in a detailed
understanding of the complex but evolutionarily con-
served set of signaling pathways through which extrinsic
factors trigger cell-intrinsic programs that regulate the life
or death of cells. Few cells are immune to the effects of
this program, thus defining a biochemical program that is
as pervasive and fundamental as many of the metabolic
pathways defined earlier in 20th century.
Making connections: from bioassays to key
molecules
The migration of neural cells [14–16]
Early in the past century, it became clear that most central
neurons arise in a transient layer, the ventricular zone, and
then migrate to their definitive nuclei or laminae before or
as they differentiate. Between 1960 and 1990, some of the
major features of this migratory process were elucidated by
Sidman, Rakic and others. One feature was that the neu-
roblasts migrate along the surfaces of radial glial
cells — cells that themselves span the thickness of the
neural tube, from ventricle to pia. In vitro studies later con-
firmed that neurons use radial glia as migratory guides.

Figure 4
Model showing how neurotrophic factor
deprivation triggers a core apoptotic pathway. Regulation of a core apoptotic pathway by neurotrophins
(a) In the presence of neurotrophins, Trk
(a) In the presence of neurotrophin
receptor signaling is thought to activate anti-
apoptotic factors of the Bcl-2 (Ced-9) class.
Activation of these Bcl-2-like proteins inhibits
the activity of Apaf-1 (Ced-4) class proteins
and blocks the cleavage of caspase (Ced-3)
class proteins. (b) Removal of neurotrophins
permits cleavage of pro-caspases and triggers
cell death. Modified from [7]. Extracellular
Intracellular
Second, in some regions — most notably the cerebral cor-
tex — there is a systematic relationship between the time
a neuron is ‘born’ (that is, exits the cell cycle) and its lam-
inar fate. In the cortex, the earliest born neurons populate
layer 6, then succeeding cohorts migrate past their older
siblings to form layer 5, then layer 4 and so on.
These phenomena imply the existence of signals on or near
radial glia that first promote migration of neuroblasts in
appropriate directions, and then arrest movement at appro-
priate locations. A major advance in the past decade has
been the identification of the first few components of this
migratory machinery. Progress has been driven in large part
by genetics: positional cloning of genes mutated in humans
and mice with cortical defects, and unexpected phenotypes
of knockout and transgenic mice generated for other nefar-
ious purposes. A particularly gratifying historical note is that
the first key molecular insights into migration came from
the isolation of a new allele of a mouse mutant, reeler, that
Sidman, Rakic and colleagues had earlier used to elucidate
cellular features of neuron–glia interactions. So, advances in
molecular technology allowed a new generation to realize
Development Jessell and Sanes 605
(b) In the absence of neurotrophin
Neurotrophin
Trk
Bcl-2 Bcl-2
Apaf-1 Apaf-1
Caspase Cleaved
caspase
(inactive) (active)
Cell survival Cell death
Current Opinion in Neurobiology
Sidman’s original hope that the mutated genes would
encode key players in the biology of CNS development.
In reeler mice, late-migrating neurons fail to pass their older
siblings, leading to a scrambling of the normal inside-out
relationship between birthdate and laminar position. The
reeler gene turns out to encode a large secreted molecule
called reelin, which is concentrated in the superficial corti-
cal laminae and seems to promote dissociation of
neuroblasts from the radial glial surface. Once reeler was
identified, further progress required an analysis of its
effects on neuroblasts. Here again, genetics has been criti-
cal: mouse mutants lacking a cytoplasmic adaptor protein,
mdab-1, and double mutants lacking two members of the
low-density lipoprotein receptor (VLDLR and ApoER2)
family have phenotypes very similar to that of reeler, and
mutants lacking integrin alpha 3 have a distinct but relat-
ed phenotype. These remarkable discoveries motivated
biochemical studies that now permit the assembly of a
rudimentary genetic pathway in which reelin is a ligand,
LDL receptors and integrins are reelin receptors, and
mdab-1 is a critical component of the intracellular signal
606 A decade of Current neurobiology

Figure 5 rapid progress in elucidating the biochemical pathway

responsible for neuronal nucleokinesis.
Control of CNS cell migration by reelin signaling
Pial surface
XXXXXXXXXXXXXXXX
As always, attempts at simplification were promptly
XXX
XXXX XXX countered by growing evidence of complexity. For many
XXXX XXX
XX
X
XX X years, it had been apparent that whereas many central
XXX

XX
neurons migrated radially along radial glia, others migrat-

X
/////////////////////////////////////////////////////////////////// Fukutin ed non-radially along other guides, including axons and
/////////// ////////
//// //////// ////// extracellular matrices. The extent of non-radial migration
/ ////// /////
////
////
was clearly great in subcortical structures such as the
//

/////
////// / /

/ / / ///
Reelin tectum, but remained a matter of controversy in the
cortex, where migration has traditionally been studied
most intensively. In the late 1990s, it was found that a
large fraction of cortical interneurons arise in subcortical
VLDLR
Neuroblast areas rather than in the cortical ventricular zone, and
Integrin migrate tangentially into the cortex. The structures and
mdab-1 molecules that guide this migratory path — a much
longer and more convoluted one than that guided by
radial glia — remain to be discovered.
LIS1
Microtubules The guidance of axons [17–24]
Doublecortin Beginning in the 1970s, studies of cultured neurons
Radial showed that neurite outgrowth is promoted and guided
glial
cell by a variety of cell-derived glycoproteins. Taken togeth-
er with Sperry’s influential chemospecificity theory,
which derived from studies of retinotectal regeneration
Ventricle in vivo, this work led to the conviction that axonal trajec-
tories are not determined by innate programs or by
mechanical discontinuities, but rather by molecular cues
Current Opinion in Neurobiology
encountered in the terrain of the growing axon.
Naturally, students of the field were eager to identify the
A proposed signaling pathway by which reelin, its receptors, and
intracellular transduction proteins arrest the radial migration of
relevant cues and the receptors used by growth cones to
cortical neurons. Migrating neuroblasts express two major classes recognize them.
of reelin receptors: members of the VLDLR/ApoER2 families of
transmembrane proteins, and β1 integrins. Migration of Initial attention focused on the neurite-outgrowth-promot-
neuroblasts towards the pial surface brings them into contact with
ing activities of short-range signals embedded in cellular
an extracelllular source of reelin, which activates reelin receptors
and triggers an intracellular transduction pathway that involves membranes and matrix. In some studies, known matrix-
mdab-1. In turn, mdab-1 signaling is thought to regulate derived proteins or cell adhesion molecules were assayed for
cytoskeletal organization in the neuroblasts. Other proteins their ability to promote outgrowth from cultured neurons. In
expressed by migrating neuroblasts, such as LIS1, doublecortin, others, growth-promoting materials were fractioned and
Cdk5 and the Cdk5 regulator p35, also contribute to the migration
of neuroblasts. extracted to isolate novel active components. In parallel, a
variety of more elaborate bioassays were devised, and these
revealed the existence of additional signals: soluble,
transduction apparatus that leads neurons to change course chemotropic factors that acted at a distance from their
when they encounter reelin (Figure 5). source; inhibitory cues that led neurites to retract, collapse
or change course; and cues present in graded amounts in
If reelin arrests migration, what propels it in the first their target field. By 1990, several candidate short-range
place? Here, the picture is less satisfactory, but analysis of neurite-outgrowth-promoting factors had been identified,
mouse and human mutants has led to the identification of such as the laminins, N-cadherin, and a few immunoglobu-
several components, including LIS1 and doublecortin lin superfamily cell adhesion molecules. The candidates
(mutated in human lissencephalies), filamin 1 (mutated were, however, few in number, and debates ranged about
in periventricular heterotopia), and cdk5 and p35 (as whether a few or a few thousand such factors remained to be
revealed by unexpected phenotypes of knockout mice). defined. Worse, there was little indication of which (if any)
In an even more striking example of the power of genet- were important, and viable candidates for inhibitory and
ics, LIS1 turns out to be homologous to the product of the chemotropic activities were nowhere to be seen.
NudC gene, which was identified in a screen for nuclear
migration defects in the mold, Aspergillus. This mold is Over the past decade, and for two main reasons, this situa-
little studied but genetically tractable, and may permit tion has changed dramatically. First, the newly established

bioassays were used in conjunction with ever-improving
biochemical and molecular biological methods to isolate
active molecules. Second, genetic studies in worms and
flies led to identification of many guidance molecules, an
astonishingly high proportion of which have turned out to
possess functionally important vertebrate orthologues. As a
result, we ended the millennium with an impressive inven-
tory of guidance cues and neuronal receptors (Figure 6).
Most turn out to be members of families of moderate size,
ranging from a few to a dozen or so members: some of the
principal ones are the semaphorins and their receptors, the
neuropilins and plexins; the netrins and their receptors,
DCC/neogenin and the Unc5s; the slits and their receptors,
the robos; and the laminins and their receptors, the inte-
grins. In addition, the larger cadherin and immunoglobulin
superfamilies grew by leaps and bounds. Most importantly,
as the decade came to an end, genetic studies in worms,
flies and mice provided evidence that a significant fraction
of these ligand/receptor pairs play critical roles in the guid-
ance of defined axonal populations. A particularly striking
illustration of the phylogenetic conservation that has pro-
pelled the field forward is that at least some similar
mechanisms (e.g. chemoattraction and chemorepulsion)
and molecules (e.g. netrins and perhaps slits) guide axonal
growth across the midline in all three species.
Among the many families of candidate guidance mole-
cules, two that were completely unknown in 1990 are
worthy of special note. First are the ephrins and their
receptors the Eph kinases (or vice versa). One member of
this family was discovered by Bonhoeffer and colleagues in
a directed search for the presumed molecular gradients on
retinal axons and their tectal targets that account for form-
ation of the retinotopic map. It was this map that led
Sperry to his chemospecificity hypothesis, so elucidation
of its molecular basis became a central question in devel-
opmental neurobiology. Results from many groups have
now shown that gradients of ephrins along the anteropos-
terior axis of the tectum and of Eph kinases along the
anteroposterior axis of the retina are among the ‘locks and
keys’ that Sperry envisioned so long ago.
Second are huge sets of G-protein-coupled receptors, dis-
covered in a search for the proteins that recognize odorants
in the nose. Genetic studies led to the riveting result that
these proteins are not only bona fide olfactory receptors but
also play critical (albeit still mysterious) roles in the target-
ing of individual subclasses of olfactory receptors to the
specific glomeruli within which they synapse on neurons
in the brain. These studies provide an inkling of a chemo-
specificity mechanism quite different from that of
molecular gradients, and raise the question of whether
maps of connectivity in different parts of the brain are con-
structed by fundamentally different mechanisms.
As we enter the new millennium, we have an embarrass-
ment of riches. Still missing is a clear picture of how even
a single axon guidance decision is determined.
Development Jessell and Sanes 607
Figure 6
Molecular mechanisms of axonal growth and guidance
+ Long-range
+ attractive
+ cues
+ +
Short-range + + (e.g. netrins)
attractive cues ++
+
(e.g. laminins) + +
+
+++
– – – – –
– –– –– –
Short-range – –
– Long-range
inhibitory cues – repulsive
(e.g. ephrins) –
cues
(e.g. semaphorins)
Current Opinion in Neurobiology
Molecular mediators of axonal growth and guidance. Four major
classes of signals contribute to the guidance of developing axons:
short- and long-range attraction and short- and long-range repulsion.
For each class, a single important molecular family is listed. Laminins
represent one major family of short-range attractive or growth-
promoting cues, netrins represent a major family of long-range
attractants, ephrins represent a major family of short-range inhibitory
cues, and semaphorins represent a family of long-range repulsive cues.
The diagram is an oversimplification in that some molecules can act as
either attractants or repellents depending on the situation. Moreover,
additional families of guidance cues and receptors for most of the
family have been identified and are listed in the text.
Nonetheless, there is a feeling abroad in the land that
many — perhaps even a majority — of the key players
have been discovered, thus providing a solid foundation
for asking biologically important questions about the
strategies that axons use to reach their targets in vivo.
The formation of synapses [25–28]
Axons can grow on their own, but it takes two cells (or
three, counting glia) to make a synapse. For this simple
reason, our understanding of how axons connect with their
targets has lagged behind knowledge of how they reach
their targets. Nonetheless, during the 1970s and 1980s,
work by Cohen, Fischbach, McMahan, and many others
documented some of the basic phenomena that underlie
this crucial process. These included the organization of
presynaptic differentiation (especially the clustering of
neurotransmitter-containing vesicles) by components of
the postsynaptic apparatus, the organization of postsynap-
tic differentiation (especially the clustering of
neurotransmitter receptors) by the nerve terminal, and the
localized synthesis of synaptic components at synaptic
sites. Moreover, several candidate organizing or inducing
molecules were identified, based on their localization or
bioactivities. Much of this work was done in vitro, and
almost all of it utilized a single, rather atypical synapse, the
vertebrate skeletal neuromuscular junction. Nonetheless,
these studies provided a basis for rapid progress during the
1990s, three aspects of which we mention here.
608 A decade of Current neurobiology
First, genetic studies in mice provided solid evidence that
some of the candidate organizing molecules do, in fact, play
critical roles in the formation of the neuromuscular junction
in vivo. Pride of place goes to agrin, a nerve-derived orga-
nizer of postsynaptic differentiation. In the manner noted
above for neuronal migration, related phenotypes of other
mouse mutants led to the elucidation of a genetic pathway:
in this case, one in which agrin is the signal, the tyrosine
kinase MuSK is (a component of) the agrin receptor, the
cytoplasmic protein rapsyn is an effector, and the dys-
trophin–glycoprotein complex (and especially its
cytoplasmic component, α-dystrobrevin) modulates matura-
tion and maintenance of the postsynaptic apparatus
(Figure 7a). By similar means, synaptic laminins have been
identified as retrograde messengers, though their precise
roles remain poorly defined. Disappointingly, none of these
molecules appear to play major roles at central synapses, but
they do provide models of a molecular and cellular logic that
may be generally applicable.
Second, in the mid-1990s, several groups initiated a direct
assault on central synaptogenesis. A key here was the
development of culture systems in which isolated
hippocampal pyramidal cells received excitatory
glutamatergic synapses from each other as well as
GABAergic synapses from nearby inhibitory interneurons.
Using these preparations, molecules essential for construc-
tion of the postsynaptic apparatus have been characterized,
including a large group of PDZ-domain proteins (including
PSD-95, Grip and Homer) at excitatory synapses
(Figure 7b) and gephyrin at inhibitory synapses. For one of
these, gephyrin, the phenotype of mutant mice confirms a
critical (rapsyn-like) clustering role in vivo.
Third, in just the past few years, the first reports have
appeared on the results of large-scale screens in worms and
flies designed to identify genes important for synapse for-
mation. The first few candidates (e.g. liprin and
highwire/rpm-1) may or may not turn out to be central
players, or lead to identification of vertebrate orthologues.
However, the enormous success of comparable screens in
identifying key players in neurogenesis, apoptosis and
axonal guidance, as mentioned above, provides ample
cause for optimism.
Making circuits: from an attractive hypothesis
to a new beginning [29—31]
Some simple behaviors, and even some moderately complex
ones, are mediated by circuits that are ‘hard-wired’ — that is,
they form in embryos without obvious need for activity or
experience. These include reflexes, motor programs, and
even some social behaviors that ethologists have shown to be
‘innate’. In contrast, more complex behaviors, including those
that seem to be most deeply human, are shaped by experi-
ence. Indeed, at least in vertebrates, experience, once
transduced into action potentials, shapes each nervous system
to the unique needs of its owner. At the intersection of devel-
opmental neurobiology and psychology is the fascinating
question of how epigenetic influences such as neural activity
interact with genetic instructions to form and modify circuits.
At the beginning of this decade, thinking about such expe-
rience-dependent rearrangement was deeply influenced
by two compelling sets of data. The first, mentioned
above, was the evidence that target-derived neurotrophic
factors affect the growth and survival of neural inputs. It
was natural to extend this neurotrophic hypothesis to
synapses, and to suggest that activity-dependent release of
related or even identical factors might provide a mecha-
nism by which activity could affect synaptic strength.
Indeed, many results were viewed as consistent with such
a ‘synaptotrophic’ mechanism.
The second data set was largely that of Hubel and Wiesel
and their students on ocular dominance, visual deprivation,
and critical periods in cats and monkeys. Their results pro-
vided seemingly irrefutable evidence that the relative
level and synchrony of activity exerted a powerful influ-
ence on brain circuitry. The implication that “neurons that
fire together wire together” was later supported by several
independent lines of evidence. Amongst this evidence was
the discovery of patterned waves of electrical activity in
retina — even before eye-opening — revealing that neu-
rons that wire together do, indeed, begin by firing
together. Taken together, then, these results led to an intu-
itively satisfying model in which synchronous presynaptic
and postsynaptic activity could couple release and uptake
of synaptotrophins, thereby weakening or strengthening
connections in rough accord with Hebb’s postulate.
Given this promising start, it is frustrating that the ‘smoking
synaptotrophic gun’ remains undiscovered, or at least unrec-
ognized. That is, despite clear evidence that neurotrophins
modulate connectivity and synaptic efficacy, their precise
role in linking activity to plasticity remains obscure.
Likewise, despite clear evidence that activity modulates
neural circuitry, there remains considerable controversy
about which of the many effects of activity are permissive
and which are instructive [32,33]. This unfulfilled state of
affairs, however, should not be grounds for discouragement:
it is little wonder that such complex, ‘systems-level’ phe-
nomena are slower to yield to cellular analysis than many of
the unitary processes discussed above. Indeed, in our opti-
mistic view, it should soon be possible to subject the
synaptotrophic hypothesis to more critical tests, and there is
every expectation that at least some of its main elements will
receive direct support.
Making medicine: from bench to biotech
Over the past decade, neurology has advanced from a dis-
cipline dominated by diagnostic rigor to one in which
therapies for previously intractable maladies can be envi-
sioned. Recent contributions of neurobiological
underpinnings of the revolution in neurology are covered
elsewhere in this issue (see the review, in this anniversary
issue, by Zoghbi, Gage and Choi [pp 655–660]). Here, we
 Development Jessell and Sanes 609

Figure 7

Proteins that control the organization of

peripheral and central synapses. (a) Agrin Proteins involved in organization of peripheral and central synapses
released by motor nerve terminals activates (a) Peripheral synapse
the tyrosine kinase MuSK to trigger
organization of the postsynaptic membrane at
Motor axon Motor nerve
the skeletal neuromuscular junction. A critical
growth cone terminal
aspect of postsynaptic differentiation is
clustering of acetylcholine receptors (AChRs) Agrin
by the cytoplasmic protein, rapsyn. Muscle-
derived organizers of presynaptic β2-laminins
differentiation are less well described, but
appear to include the β2-laminins. (b) A
glutamatergic synapse in the brain may
contain multiple receptor subtypes (i.e. MuSK AChR rapsyn
NMDA, AMPA/kainate, and metabotropic),
each of which is associated with putative
clustering proteins, many containing PDZ
domains. Roles of specific organizing
(b) Central synapse
molecules remain to be determined, but at
least three links between pre- and Presynaptic
postsynaptic membranes have been proposed terminal
to play critical roles: cadherin—cadherin,
CASK
neuroligin—neurexin, and ephrin—Eph kinase.
MINT Ca2+ ephrin
Cadherin channel
Neurexin

mGluR
Cadherin AMPAR NMDAR Eph
Neuroligin kinase Homer
Postsynaptic
terminal GRIP PSD-95
Shank
GKAP
GRASP
Current Opinion in Neurobiology

note briefly three advances that have come directly from
basic research in neural development.
Stem cells [34]
Stem cell biology is very much in the news these days, and
there is considerable optimism that it will be possible to
direct the differentiation of progenitor cells along predefined
and therapeutically relevant pathways of differentiation. To
realize this potential, it is important to establish a set of rele-
vant progenitor cell characteristics and behaviors. During the
past decade, developmental neurobiologists have begun to
achieve this aim for neural progenitors. It is now clear, for
example, that embryonic progenitor cells can differentiate
into postmitotic neurons in an adult environment. In addi-
tion, the mature mammalian CNS also appears to contain
progenitor cells; these are normally relatively quiescent but
can be goaded into proliferative activity by insult in vivo or
by exposure to mitogenic factors in vitro. Moreover, some of
these cells can even differentiate into neurons when reintro-
duced into the adult CNS.
Although these advances are exciting, many key issues
remain unresolved. First, the origin of adult CNS stem cells
remains a matter of debate. Are such cells of ependymal or
radial glial origin, or both? Second, with the possible excep-
tion of neural crest stem cells, it is not yet feasible to control
in any rational way, the pathway of differentiation of such
progenitor cells, of either embryonic or adult origin. Third,
for neurodegenerative disorders involving projection neurons,
it is not clear how reintroduction of a newly generated neu-
ron will solve the problem of long-distance axonal growth
and selective synapse formation in an adult environment.
Here, advances in nerve regeneration may have to proceed
hand in hand with the new stem cell biology. Despite these
reservations, only the most reactionary of developmental
neurobiologists would deny the intriguing and perhaps enor-
mous potential of applied stem cell research to the treatment
of degenerative disorders of the nervous system.
Apoptosis [13]
The realization that many neural insults unleash a com-
mon biochemical cell death program and the elucidation of
the sequential steps in this pathway have enormous thera-
peutic potential for the treatment of neurotrauma and
neurodegenerative disorders. This point has not been
overlooked by the pharmaceutical and biotech industries,
and the design of caspase inhibitors and Bcl-2 activators
has reached a chemical sophistication that is likely, in the
610 A decade of Current neurobiology
near future, to herald the introduction of the first anti-
apoptotic drugs. Just how useful these compounds will
prove to be again remains a matter of conjecture, but it is
hard to imagine that the diversity of small molecule targets
revealed through elucidation of the biochemical compo-
nents of the cell death pathway will not have some
practical outcome.
Developmental diseases [14,35]
As noted above, the past decade has witnessed the identifi-
cation of genes that control cortical migration — for example,
the genes responsible for heterotopias and lissencephalies.
Likewise, a few congenital neurological diseases have now
been found to result from mutations of genes that encode
axon guidance molecules. Defining the function of these
genes is likely to require a more profound appreciation of the
normal mechanisms of cortical development. If we achieve
this level of understanding, there is the possibility of provid-
ing satisfying cellular and molecular explanations of the role
of developmental defects in cognitive disorders — Williams
syndrome, for example, or, conceivably, even schizophrenia
or autism. These are distant and daring goals certainly, but
goals that are clearly visible and thus worth striving for.
Why was progress rapid but uneven?
What has enabled such spectacular progress in developmen-
tal neurobiology over the past decade, and why have most
advances been concentrated in early developmental epochs?
The answer to both questions, in a word, is the gene or, in
two words, genetics and genomics — the technologies that
are built around the gene. At a conceptually trivial but prac-
tically important level, techniques such as expression
cloning and recombinant protein production have freed
molecular neurobiologists from the tyranny of protein purifi-
cation. Now, database mining is taking us a step further.
Perhaps more importantly, advances in genetics and
genomics have played the leading role in making plain
the shared developmental mechanisms used in diverse
tissues and in different organisms. Three striking types of
conservation have been discussed in the body of this
review but can be restated here in more succinct form:
1. Bones are kidneys are brains — at least with
respect to their programs of induction and differ-
entiation; as illustrated by the commonality of use
of Wnt, hedgehog, FGF and BMP signals.
2. Flies are worms are vertebrates — at least as illus-
trated by their common programs of regionalization,
neurogenesis, apoptosis and axon outgrowth.
3. Mice are people — as is already clear from genome
sequencing and the conserved function of known
genes. In this regard, the mouse is likely to remain
a powerful experimental organism for testing the
function of genes implicated in the development
of the human nervous system.
We believe that the most stunning advances of the past
decade may be the deep appreciation and exploitation of
this remarkable conservatism. This alone goes a long way
toward explaining the advances we have summarized, and
also helps to explain the inverse relationship that exists
between developmental stage and our understanding of
mechanisms of neuronal differentiation at the end of the
1990s. The challenge for the next decade is to redress this
imbalance and in the process, hopefully, to provide a com-
pelling account of the entire spectrum of events that control
the assembly of neural circuits in the mammalian brain.
Acknowledgements
We thank the many colleagues who took the time to respond to our
invitation to provide us with their views of the important advances of the
1990s. While we have failed to represent adequately the entire spectrum of
opinion that emerged, their responses were influential in shaping and
limiting the scope of this review. Indeed, the seven areas on which we chose
to focus were those most often mentioned by this group.
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