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

84 NORMA L DEVELOPMEN T
FIGUR E 5- 8 Effec t o f lysophosphatidi c aci d (LPA ) on
cortica l development . Intac t cerebra l hemisphere s ex -
posed t o (LPA ) e x viv o exhibi t cortica l foldin g an d
widenin g of the cerebra l wall compare d t o contro l hemi -
spheres fro m th e sam e animal . Whole-moun t view s (A)
and sagitta l section s (B ) fro m gestationa l da y (G ) 1 4
hemisphere s sho w dramati c cortica l foldin g followin g
cultur e with LPA, compared t o contro l medium . D, dorsal;
R , rostral ; Ctx , cortex ; GE , ganglioni c eminence .
Scale ba r = 0.50 mm . C . G1 4 cortice s labele d with th e
nuclea r stain DAP I show increase d thicknes s following
cortica l thickness , mitosis , an d cel l surviva l ar e ob -
served i n LPA 1 /LPA 2 recepto r nul l mic e (Kingsbur y et
al., 2003) , result s demonstratin g tha t th e effect s o f
LPA in an ex vivo system ar e recepto r mediated .
The rapi d increas e i n cortica l siz e followin g LPA
exposure i s consisten t wit h studie s showin g tha t res -
cue o f V Z cel l death—likel y multipl e round s o f
death , given th e ~2-hou r clearanc e tim e estimate d for
dying cell s i n th e corte x (Thomaido u e t al. , 1997 ) —
can hav e majo r consequence s fo r cortica l growt h
(Kuid a e t al. , 1996 ; Pompeian o e t al. , 2000) . More -
over, th e increase d presenc e o f postmitoti c neuron s
(β-tubulin-III-labele d cells ) in th e VZ followin g LPA
treatmen t ma y represen t prematur e differentiatio n of
NPC s tha t contribut e to increase d VZ thickness . Th e
switch t o a postmitoti c statu s coul d trigge r th e pro -
ductio n o f suppressor protein s (i.e. , Bcl-x L) able t o abrogate
PC D in cells migratin g from VZ t o CP.
LPA signalin g ca n hav e majo r effect s o n cell s
within th e embryoni c cerebra l corte x that are distinct
LPA-treatment . CP , cortica l plate ; IZ , intermediat e
zone; SZ , subventricula r zone ; VZ , ventricula r zone .
Scale bar=100μm . LP A promote s termina l mitosi s
throug h a n increas e i n M-phas e cell s immunolabele d
with anti-phosphohiston e H 3 antibod y (D) , a decreas e
in S-phas e cell s (dat a no t shown) , an d a n increas e i n
differentiatin g neuron s immunolabele d wit h anti-β -
tubulin II I antibody (E) . LP A decreases th e numbe r o f
dying cells immunolabele d for anti-activ e caspase-3 antibody
(F) . (Source: Modifie d fro m Kingsbur y e t al ,
2004)
from cel l proliferation . Interestingly , th e foldin g pat -
tern observe d i n brain s treate d wit h LP A are superfi -
cially reminiscen t o f thos e observe d i n hyperplasti c
brains from knockou t mice fo r caspase s (Kuid a et al.,
1996; Rot h e t al., 2000) or PS R (L i et al., 2003). De -
spite thes e similarities , LPA-mediate d cytoarchitec -
toni c change s diffe r fro m thos e of caspase deletio n i n
several aspects . Disruptio n o f cel l deat h b y caspas e
deletio n result s in reduce d NP C deat h an d increase d
VZ siz e withou t a marke d increas e i n C P thicknes s
(Kuid a e t al., 1996 ; Hayda r et al., 1999b ; Pompeian o
et al. , 2000). Augmente d cel l cycl e re-entr y by over -
expression o f β-cateni n produce s fold s vi a th e tan -
gential expansio n o f cortica l surfac e are a withou t
increase s in cortica l width (Chen n an d Walsh, 2002 ;
Zechne r e t al. , 2003) . B y comparison , receptor -
mediate d LP A signaling increase s cortica l thicknes s
by alterin g bot h proliferativ e and postmitoti c popula -
tions, an d furthe r produce s regularl y arrange d corti -
cal folds .