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

FIGURE 5- 7 Aneuploi d cell s i n th e adul t corte x are
neurons. A . Th e presenc e o f bot h microtuble -
associated protein (MAP ) 2-positive (large arrow) an d
MAPZ-negative (smal l arrows ) cells i n a 1 0 Jim sec -
tion throug h adul t cerebra l corte x demonstrate s th e
specificity o f MAP 2 labelin g a s a neurona l marker .
Nuclei wer e counterstained wit h DAPI . B-G . Cell s
in 1 0 ^Lm sections through the adult male cortex were
hybridized wit h X and Y chromosome paints . C , E ,
G. Cell s i n these same 1 0 \im sections were then im -
munostained for MAP2. B. The cel l o n th e lef t con -
tains bot h a n X and a Y chromosome (note d b y a n
asterisk), whereas the cel l on the righ t has an extra Y
chromosome. C. The cel l with two Y chromosomes is
MAP2-positive. D, E. A cell in motor cortex contains
an extr a X chromosom e (D ) an d i s MAP2-positiv e
(E). F, G. A cell i n motor corte x contains a n extr a Y
chromosome (F ) an d i s MAP2-positiv e (G) . Scal e
bars =10 Jim (D , F ) an d 5. 0 Jim (H , J) . (Source:
Adapted from Rehe n e t al., 2001)
CELL DEATH 8 3
Some trophi c factor s suc h a s fibroblast growth facto r
2 (FGF-2 ) an d NT- 3 ar e als o known to regulate th e
transition fro m dividin g NPCs to terminally differen -
tiated neuron s in the CNS , (Ghos h an d Greenberg,
1995). Tha t said , factor s abl e t o modulat e PC D
within the VZ are less well understood .
A lipid molecule, lysophosphatidic acid (LPA), has
been implicate d i n th e regulatio n o f neurogeneti c
processes, including proliferative cell death. Man y of
the effect s o f LPA are mediated by G protein-coupled
receptors tha t ar e member s o f the lysophospholipi d
receptor gen e famil y (Fukushim a e t al., 2001 ; Chun
et al, 2002 ; Anlike r an d Chun , 2004 ; Ishi i e t al,
2004). A role for LPA signaling in nervous system development
wa s initially suggested b y the discover y of
the firs t lysophospholipi d receptor , LPA 1? whic h
shows enriche d expressio n in th e V Z (Hech t e t al. ,
1996). Subsequen t studie s hav e identifie d LPA 2 ex -
pression i n postmitotic cell s o f the embryoni c cortex
(Fukushima et al, 2002; McGiffert e t al., 2002) and
LPA3 expressio n withi n th e earl y postnata l brai n
(Contos e t al. , 2000) . LPA , i s als o presen t i n th e
brain (Das and Hajra, 1989 ; Sugiur a et al, 1999 ) an d
can b e produce d b y postmitoti c neuron s an d
Schwann cell s i n cultur e (Weine r an d Chun , 1999 ;
Fukushima e t al.,2000).
In a n e x vivo brain culture system , LPA exposure
rapidly alters the organizatio n of the developing cere -
bral corte x (Kingsbur y et al. , 2003) . Afte r jus t 1 7
hours, LPA-treated hemispheres displa y striking cortical
fold s an d a widenin g o f the cerebra l wall , com -
pared t o untreate d opposit e hemisphere s obtaine d
from th e sam e animal s (Fig . 5-8 ) (Kingsbur y et al. ,
2003, 2004) . This expansio n o f cortica l thickness is
due t o a n increas e i n cell s within bot h proliferative
and postmitoti c region s withou t a correspondin g
change i n cell density. Whereas LP A is a mitogen for
many cell types in culture (Moolenaar , 1995 ; Moolenaar
e t al. , 1997) , LP A exposure appears to decrease
proliferation i n a n e x vivo brain culture syste m in favor
of terminal mitosi s (Kingsbury et al., 2003). In addition,
LPA exposure in this ex vivo system promotes
the surviva l o f VZ cells . Therefore , th e increas e i n
cortical thicknes s followin g LP A treatmen t i s du e
to (1 ) the increase d surviva l of many NPCs , whic h
enlarges the proliferating pool, and (2 ) the inductio n
of termina l mitosis , which increase s the numbe r o f
postmitotic neurons. Most importantly from a mechanistic
standpoint , neithe r foldin g no r increase s i n