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.• SeD .. AN D PAUL] . LOMBROSO. M .D.

Laboratories around the world are explo ring th e intricacies of

how the human central nervou s sys tem devel ops. Under­

stand ing the mechan isms of corti cal development gives

essential insight into the pathogenesis of man y genetic and

acqu ired devel opmental psychiatr ic di sorders. including

autism. sch izophrenia . and learning d isabilit ies. O ver th e next

several months. this column will h ighlight aspects of normaland ab no rma l cort ica l development. We will report onrecently isolat ed molecules th at have been di scovered to par­

ticipate in brain growth and devel opment. We will discussthe func 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.

Neurons of the ce rebral co rtex form a highly organized

laminar and radial str uct u re. The ad ult human co rt ex is

charac terized by six layer s. each co ns ist ing of spe cial ized

neurons with specific phenot ypes and syna ptic connections

(Fig. IA ). Although in most organs . cells are born near their

event ual location. in th e embryonic de velopment of theco rtex. neurons are generat ed some dist an ce away. The final

m igration of the se neurons and the establishment of proper

interneuronal connections are critical for proper cortical

fun ctioning. Defects in this dynamic process underlie a

number of developmental di sorders of higher bra in function.The first neurons dest ined to settle in the human cortex are

produced during the first half of gestation. deep within thebrain and close to the cavity of the cerebral ventricle in a

region called the ventricular zone. Shortly after their lastmitotic d ivision s. these neurons migrate outward toward the

pial surface of the cortex. where they form a sheet of cells

called th e corti cal plate. Each successive gen eration of

migrating neurons passes through the previously born cells

before arr iving at 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 ofrad ial glial cells (Fig. IC) as a scaffold ing to aid thei r nav-

A B c

Tra Ing Process

-' LeadingProcess

_ RadialGlialProcess

- MigstingNeuron

VentricularZone

Cortical Plalo.,',

~ PIal Surface

~~~RMarglnal Layer

Radial _Glial Process

Ra alMigratingCell-

Noel-RadiallyM'graling Co

Racial GilCe Body ___

RadialG lia

Fig . 1 Nor mal development of the cerebra l cortex. (Al Sect ion throug h the developin g pr imate forebrain sbowing

d istrib uti on paHern of radial glial pro cesses th at span feta l cereb ral wall from the ventricle to the pial surface. (B)

Enlargement of the boxed area in (A) to illustra te how neurons migr ate from their birth place in the vent ricular zone

aero" the intermediate zone [0 their final destination 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. FromRaki c P ( )972). Mo de of cell migration to the superfic ial layers of feral monkey neocortex. J Comp Neurol1 4~:(' I -!U. copyright © 1972. John Wi ley & Sons.

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

igation. These cells form long fascicles that span the cerebralcortex and guide the migrating neurons through each cort icallayer. According to the radial unit hyp othesis of conicaldevelopment, the horizontal location of con ical neuron isdetermined by the position of its precursor cells in the prolif­erative ventricular zone, while its depth result s from its birthorder.

This pattern of development has two major con sequences.First, the corte x develops in an inside-out pattern in whichthe earliest-born neurons are found in the deepest conicallayers and th e later-born neurons mo ve to the moresuperficial layers. Second, the radial glial hypothesis providesan explanat ion for the columnar organizat ion of the cortex.Each group of progenitor cells with in the ventricular zonegives rise to a column of interrelated neu rons above it. Afterthe neurons have taken their proper laminar positions, theydevel op characteristic synapti c connections with nearbyneurons as well as more distant neurons in associated region sof the cortex.

Di sruptions of neuronal migrat ion have been found inseveral developmental disorders, such as lissencephaly andmovement disorders (such as the reeler mutation in mice).The molecular basis for these disorders will be discussed inthe next two columns. In addition, more subtle disruptions ofmigration 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 disorders such asdyslexia and psychosis.

WEB SITE OF INTEREST

hllp:l l info.m ed .yale.edu/n euro biolr ak icl raki c. html (visit thi s site on theInte rne t depicting anima ted version of cellula r events dur ing early corti­

cal developm ent)

ADDITIONAL READINGS

Hatten M (1993), T he role of migration in cent ral nervous system neuronal

development . Curr Opin Neurobiol.L~8-44Levitt P. Barbe M . Eagleson K (1997), Patt ern ing and specificatio n of th e

cereb ral cortex. Annu Ra Neurosci 20 :1-2 4

Mountcastle V (1997), The colum nar organizatio n of the neoco rtex. Brain

120:70 1- 72 2Rakic P (1988) , Specification of cerebral con ical areas. Scimce 241 :170-176

Rakic I' (1995), Radial versus tangent ial migration of neu ronal clones in the

developing cerebral cort ex. Proc Na t! Acad Sci 92 :11323-11.327

Acapud july 25. 1997.Dr. Rakic is l'roJfssorand Chairman, Neurobiology, ~;dr Unit'rrsiry School of

Medicine, Neio Ha ven, C T Dr. Lomb roso is Associate Professor. Child Stud,y

Center. };dr Uui l'rrsiry School ofMedicine.

Correspondence to Dr. Lombroso, Child Stltdy Center. Yale University School

ofMedicine, 230 Sou th Frolllagr Road. Nr ui Haren, CT 06520.

0890-8567/98/3701 - 0 116/$0.300/01\)1998 by th e American Academ y ofC hild and Ado lescent Psychia try.

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