Brain Development: Normal Processes and the Effects of Alcohol ...

76 NORMA L DEVELOPMENT
postmitotie, or die. Those neurons that become postmitotic,
a step referred to as the birth of a neuron, migrate
ou t o f th e VZ , throug h a superficia l regio n
termed the intermediate zone (IZ) , until they reach a
position i n the superficia l aspec t o f the anlag e o f the
cortical gra y matter known as the cortical plate (CP) .
Once i n th e CP , neuron s differentiat e an d mak e
synaptic connection s (Miller , 1988 ; Baye r an d Alt -
man, 1991 ) o r di e (e.g. , Finla y an d Slattery , 1983 ;
Miller, 1995) .
Death of Post-Mitotic Cells
Historically, on e reaso n th e contributio n o f PCD t o
development ha s no t bee n well-recognize d i s tha t
apoptotic bodie s ar e susceptibl e t o rapi d clearanc e
and phagocytosi s in intac t tissue. Thus, it is difficul t
to study the presenc e of cell death in static (fixed) tissue.
A real-time approach could unequivocally determine
the prevalence an d distribution of dying cells in
situ, however , thi s metho d i s not currentl y practica l
since e x viv o system s produc e artifactua l change s
in cellular behavior and induce premature cell death.
Approximately one-third or more of the post-mitotic
neuronal populatio n undergoe s naturall y occurrin g
PCD during development relate d to insufficient acces s
to trophic signal s (e.g. , NG F an d BDNF ) fro m tar -
gets an d afférent s (Oppenheim , 1991 ; Linden ,
1994). Th e amoun t o f neurona l deat h varie s wit h
time, location , an d cel l typ e (e.g. , Miller, 1995) . I n
cortex, fo r example , th e incidenc e o f deat h amon g
different population s o f post-migrator y neurons ca n
vary fro m 10 % to 60% . Neurons i n th e deepes t an d
most superficia l corte x ar e mor e likel y t o di e tha n
those i n mid-cortex. Moreover , local circuit neuron s
within a particular layer are twice as likely to die relative
to laminar-cohort projection neurons.
PCD play s a crucia l par t i n th e developmenta l
strategy of the cerebra l cortex. An overabundance of
neurons i s generated t o create a transient scaffol d fo r
the developing cortex and i s subsequently eliminate d
as th e corte x matures . Durin g developmen t o f th e
mammalian telencephalon , th e genesi s o f neuron s
destined for the si x layers of the cerebra l cortex is preceded
b y generation o f a population o f neurons tha t
reside in the subplate (an anlage of the white matter )
and the marginal zone (the anlage of cortical layer I).
These neuropeptide-containin g neuron s (Chu n
et al, 1987 ; Al-Ghoul and Miller, 1989 ; Ghosh e t al,
1990) ar e presen t i n larg e number s durin g
development an d functio n i n early synaptic circuitry
(Chun an d Shatz , 1989a ; 1989b) . A s the brai n ma -
tures, their disappearance through neuronal death occurs
in concert with the invasio n of the cortica l plat e
by axona l projection s an d wit h th e eliminatio n o f
synapses i n th e subplate . Thes e observation s sugges t
that during development the subplate (a) is a transient
synaptic neuropil (Chu n e t al., 1987) ; and (b ) serves
as a guidepos t fo r ingrowin g thalamocortical axons
subsequently eliminate d b y cell death . Thi s ide a o f
sculpting the cortex through an initial overproductio n
of neurons followed by paring back is in concert with
the neurotrophic theory.
Most studie s on PC D i n th e centra l nervou s system
(CNS ) hav e focused o n th e period o f target in -
nervation (se e below) , whe n differentiatin g neuron s
are sendin g out axon s and makin g synaptic connec -
tions with postmitotic neurons (Hamburger and Levi-
Montalcini, 1949 ; William s and Smith , 1993 ; Miller,
1995). An implicit assumption o f many of these studie s
was that PC D playe d a minor rol e during embryoni c
CNS development . Indeed , elaborat e mathematica l
models have been constructed that assume there is no
PCD durin g neuronogenetic phases of development
(Cavinessetal., 1995) .
Death of Proliferating Cells
Death ca n affec t proliferatin g populations of cells, a
phenomenon representin g a distinct for m an d phas e
of cell death i n the developing CNS. Thi s populatio n
is bes t represente d b y neura l progenito r an d ste m
cells (NPCs). These cells, which have morphological
and molecula r characteristic s o f radia l gli a (Nocto r
et al., 2001), are located i n the VZ and SZ. They also
share similarities with mitotic immune cell s such as T
cells of the thymic cortex (Chun, 2001). Importantly,
NPCs d o no t hav e synaptic contacts a t thi s stag e of
development, and are still proliferative.
Thymic T cells are notable a s a comparison popu -
lation t o NPCs. Developin g T cell s underg o severa l
distinct cell selection mechanism s (positive selection,
negative selection , an d deat h b y neglect) tha t resul t
in elimination of 97% of the developin g T-cell popu -
lation (Egerto n e t al, 1990 ; Shortma n e t al. , 1990 ;
Shortman an d Scollay , 1994) . Nevertheless , fo r de -
cades controversy existed following the proposal of intrathymic
cel l deat h (Metcalf , 1966) , becaus e o f th e
absence o f histological evidence fo r intrathymic cell
death (Post e an d Olsen , 1973) . I t wa s not unti l th e