DEVEL OPM ENT AND N EUR OBIOLO GY Assistant Editor: Paul j. Lombroso, M.D.

Development of the Cerebral Cortex:

1. Forming the Cortical Structure
PASKO RAKI C, M .D.• Se D .. AN D PAUL] . LOMBROSO. M .D.

Lab or atories arou nd the world are explo ring th e intricacies of
how the human central nervou s sys te m devel ops. U nde r-
stan d ing the mech an isms of corti cal d evel opment gives
essential insight into the pathogenesis of man y genetic and
acqu ired devel opm ent al p sychiatr ic di sorders. including
autism. sch izo phrenia . and learning d isabilities. O ver th e next
several months. this column will h ighlight aspe cts of normal
and a b n o r ma l cort ica l developm ent. We will rep ort on
recently isolat ed molecules th at have been di scovered to par-
ticipate in br ain growth and devel opment. We will dis cuss
the fu nc tio ns of th ese proteins and how mutations in them
disrupt the normal developmental trajectory of the chi ld ren
we see in our offices.
N eurons o f the ce reb ral co rt ex form a highly organized
lamin ar and radial str uct u re. The ad u lt human co rt ex is
ch a rac te rized by six layer s. each co ns ist ing o f spe cial ized
neurons with specific phenot ypes and syna ptic connections
(Fig. IA ). Although in most o rgans . cells are born near their
eve nt ual location. in th e embryonic de velopment of t he
co rtex. neurons are generat ed some dist an ce awa y. The fin al
m igration of the se neurons and the establishment of proper
interneuronal connections are critical for proper cortical
fun cti oning. Defects in this d ynamic proce ss underlie a
number of developmental di sorders of higher bra in functi on.
The first neurons dest in ed to settle in the human co rtex are
produced during the first half of gestation. deep within the
brain and close to the cavity of the cerebral ventricle in a
region called the ventricular zone. Shortly after their last
m itotic d ivision s. these neurons m igrate outward toward the
pial surface of the cortex. where they form a sheet of cells
called th e corti cal plate. Each su ccessive gen eration o f
m igrating neurons passes through the previously born cells
before arr iving a t the final de stination at the interface
between the co rt ical plate and the marginal zone (Fig. I B).
During migration. neuron s use a transient population of
rad ial glial cells (Fig. IC) as a scaffold ing to aid thei r nav-

A B c
~ PIal Surface
-' Leading
~~~R Marglnal Layer Process

,
.,' Cortical Plalo

Radial _ _ Radial Glial

Glial Process Process

Ra al
- Mig sting
Migrating Cell- Neuron

Noel-Radially
M'graling Co
Racial Gil Tra Ing Process
Ce Body ___
RadialG lia Ventricular
Zone

Fig . 1 Nor ma l developme nt of the cerebra l cortex. (Al Sect ion throug h the developin g pr im ate foreb rain sbowing
d istrib uti on paHern of radial glial pro cesses th at spa n feta l cereb ral wall fro m the ventricle to the pial surface. (B )
Enlargement of the boxed area in (A) to illustra te how neu rons migr ate from th eir birth place in the vent ricular zone
aero" the intermediate zone [0 their final destinatio n at the int erface betw een the marginal zone and th e develop ing
conical plate. (C) Neuroblasts use the surface of elon gated rad ial glial fibers as a gu ide during their mig ration. From
Raki c P ( )972). Mo de of cell m igration to the superfic ial layers of feral monkey neocortex. J Comp Neurol
1 4~:(' I -!U. copyright © 1972. Jo hn Wi ley & Sons.

116 J. AM . ACAD . C H ILD ADOLES C . PSYCHIATRY , .\7 :1, JAN UARY 19 98


igatio n. These cells form long fascicles that span the cerebr al
cortex and guide the migrating neurons through each cortical
layer. According to the radial unit hyp othesis of coni cal
development, the horizontal location of con ical neuron is
determined by the position of its precursor cells in the prolif-
erative ventricular zone, while its depth result s from its birth
order.
Th is pattern of development has two major con sequences.
First, the corte x develops in an inside-out pattern in which
the earliest-born neurons are found in the deepest conical
layers and th e later-born neurons mo ve to the m ore
superficial layers. Second, the radial glial hypothesis provides
an explan at ion for the columnar organi zation of the co rtex.
Each group of progenitor cells with in the ventricular zone
gives rise to a column of int errelated neu rons above it. After
the neurons have taken th eir proper laminar position s, they
devel op characteristic synapti c connections with ne arby
neurons as well as more distant neur on s in associated region s
of the co rtex.
Di sruptions of neuron al m igrat ion have been found in
several developmental disorders, such as lissencephaly and
movement disorders (such as the reeler mutation in mice).
The molecular basis for these disord ers will be discussed in
the next two columns. In addition, more subtle disruptions of
migration and in the development of synaptic connections
J . AM . AC A D . C HI L D A D OI.ES C. PS YC H IATR Y, .H :1. J ANUA RY 19 98
DEV ELOPM ENT AND NE URO BI O LO GY
have been proposed for more co mmo n di sorders such as
dyslexia and psychosis.
WEB SITE OF INTEREST
h llp :ll info.m ed .yale.ed u/n euro biolr ak icl raki c. html (visit thi s sit e o n the
Inte rne t d epicti ng anima ted version of cellula r events dur ing early corti-
cal de velopm ent)
ADDITIONAL READINGS
H atten M (1993), T he role of migration in cent ral nervous system neuronal
develop ment . Curr Opin Neurobiol.L~8-44
Levitt P. Barbe M . Eagleson K (1997), Patt ern ing and specificatio n o f th e
cereb ral co rtex. Annu Ra Neurosci 20 :1-2 4
Mountcastle V (1997), The colum nar o rgan izatio n of the neoco rtex. Brain
120:70 1- 72 2
Rakic P (19 88) , Specification of cere bral con ical areas. Scimce 241 : 170-176
Rakic I' (1995), Radi al versu s tangent ial migratio n of neu ronal clones in the
developing cereb ral cort ex. Proc Na t! A cad Sci 92 :11323-11.327
Acapu d july 25. 1997.
Dr. Rakic is l'roJfssorand Chairman, N eurobiology, ~;dr Unit' rrsiry School of
Medicine, Neio Ha ven, C T Dr. Lomb roso is Associat e Professor. Child Stu d,y
Center. };dr Uui l'rrsiry School ofMedicine.
Correspondence to Dr. Lombroso, Child Stltdy Center. Yale Uni versity School
ofMedicine, 230 Sou th Frolllagr Road. Nr ui Haren, CT 06520.
0890-85 67/98/3701 - 0 116/ $0 .30 0 /01\)1998 by th e American Acad em y of
C h ild and Ado lescent Psychia try.
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