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

Future studie s that involv e the inhibitio n o f specific
G-protein s an d downstrea m effector s i n cortical
progenitors should provid e insight int o how receptor -
mediated LP A signalin g promote s termina l mitosi s
and cel l surviva l i n th e developin g cerebra l cortex .
Such studie s may also reveal links between cell death
and suppresso r proteins , includin g thos e relate d t o
V(D)]/NHEJ an d Bcl- 2 family molecules, fo r the survival
an d prope r functio n of newly postmitotic neu -
rons within the developing brain.
CONCLUSIONS
Tissue homeostasi s i s currentl y viewed a s a carefu l
balance betwee n proliferatio n and cell death . Th e
number, compositio n an d distributio n o f cells within
both adul t an d developin g organs , includin g th e
CNS, critically depend o n this balance. The dramatic
increase i n cerebra l cortica l siz e acros s mammalia n
evolution is paralleled by increased cell numbers and
an expansio n of cortical surface are a due t o change s
in th e regulatio n o f proliferation, differentiation and
PCD withi n th e feta l brai n (Raki c an d Caviness ,
1995; Caviness et al, 1995 ; Kuda et al 1996 ; Ceccon i
et al, 1998 ; Yoshida et al, 1998 ; Hayda r et al, 1999b ;
Pompeiano e t al, 2000; Roth e t al, 2000; Chenn and
Walsh, 2003 ; Li et al, 2003). The presen t chapte r focused
o n th e rol e o f PC D i n shapin g th e develop -
ment of the cerebral cortex .
Collectively, th e result s discusse d i n th e presen t
chapter indicate that in the developing CNS, PC D is
a significant cell fate for proliferating NPCs, and thi s
PCD coul d b e responsibl e fo r a selectio n proces s
based o n alteration s o f DNA , particularl y involving
chromosomal aneuploidy . During migration and initial
differentiation, cell death i s prevented o r delayed
by th e expressio n o f suppresso r proteins, includin g
members o f th e Bcl- 2 famil y an d th e V(D)J/NHEJ
factors, thus allowing these newly postmitotic cell s to
find their final positions and differentiate. After reach -
ing thei r fina l destination , neural cell s start to com -
pete fo r limite d trophi c facto r suppor t t o surviv e
another roun d o f PCD. A newly identified group of
factors tha t affec t NPC s ar e th e lysophospholipid s —
small lipi d signal s actin g throug h cognat e G pro -
tein-coupled receptors . LP A signalin g result s i n
decreased cel l deat h an d induce d cel l cycl e exit ,
which can be considered new influences on cerebral
cortical growth and anatomy. Future studies will better
CELL DEATH 8 5
define th e mechanism s o f selectio n an d cel l deat h
during nervous system development.
Abbreviations
APAF apoptoti c protease-activating factor
BDNF brain-derive d neurotrophic facto r
BH bcl- 2 homolog y
BrdU bromodeoxyuridin e
CNS centra l nervous system
CP cortica l plat e
DNA-PKcs DNA-dependen t protei n kinas e cat -
alytic subunit
FGF fibroblas t growt h factor
G gestationa l day
ISEL i n situ end-labeling
IZ intermediat e zon e
Lig I V ligas e IV
LPA lysophosphatidi c acid
MAP microtuble-associate d protei n
NBL neuroblasti c layer
NGF nerv e growth factor
NHEJ nonhomologou s end-joining
NPC neura l progenitor cell
NT neurotrophi n
PCD programme d cel l death
PSR phosphatidylserin e receptor
SKY spectra l karyotyping
SZ subventricula r zone
trk tyrosin e protein kinase
VZ ventricula r zone
ACKNOWEDGMENTS W e ar e gratefu l t o Am y Yang ,
Marcy Kingsbury, Brigitte Anliker, Christine Paczkowski,
and Suzanne Peterson for the critical reading of this manuscript.
This work was supported by the National Institute
of Mental Health, National Institut e for, and Pe w Latin
American Program in Biomedical Sciences.
References
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Development 117:29-43.