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

190 ETHANOL-AFFECTE D DEVELOPMENT
Dissociated cultures provide model systems to illuminate
th e effect s o f FGF-2 on proliferating populations.
Cell cycle kinetics among B104 cells is affected
by FGF-2 (Luo and Miller, 1997a) . The Tc and GF
are equally affected b y FGF-2. These data are consistent
with the mixe d expression of FGF-2 response by
VZ and SZ cells. Other preparation s that presumably
model V Z and S Z cells impl y that FGF- 2 promote s
the proliferation of VZ and SZ derivatives (Martens et
al., 2000, 2002).
The effect s o f ethano l o n FGF-2-mediate d cel l
proliferation ar e not well understood. Studie s explor -
ing thi s interactio n hav e examine d C 6 gliom a cell s
(Luo an d Miller , 1996 ; Mille r and Luo , 2002a ) and
telencephalic neuroepithelial cell s (Ma et al., 2003).
They sho w tha t ethano l eliminate s th e FGF-2 -
promoted increas e i n cell proliferatio n such tha t th e
effects o f FGF-2 and ethanol nullif y each other .
The depressiv e effect s o f ethano l ar e mediate d
through th e FGF- 2 receptor , fl g (Lu o an d Miller ,
1996b, 1997b) . ER K phosphorylation, a downstream
event of flg activation, increases i n cortica l astrocyte s
(Smith an d Navratilova , 2003 ) an d ste m cell s (M a
et al. , 2003 ) treate d with ethanol . Althoug h ethano l
does not alter protein expressio n of FGF-2 receptors,
ERK activity remains elevated, implying that ethano l
affects recepto r phosphorylation .
Insulin-like Growth Factor-1
Prenatal exposure to ethanol inhibition of intrauterine
and early postnatal growth correlates with the effec t of
ethanol o n the IGF system (Breese et al, 1993 ; Sing h
et al., 1994) . Ethanol halves plasma IGF-1 content i n
the pregnant dam (Singh et al., 1994; Breese and Son -
ntag, 1995 ) and in the fetal brain (Singh et al, 1996) .
Data o n the effect s o f prenatal exposur e to ethanol o n
IGF-2 are mixed. One repor t states that the amount of
IGF-2 is doubled (Brees e and Sontag , 1995) , whereas
others sho w tha t IGF- 2 expressio n i s halve d (Sing h
et al., 1994 , 1996) . Likewise , the effec t o f ethanol o n
binding protei n (IGF-BP ) i s als o mixed . Som e evi -
dence show s tha t IGF-B P expressio n i s reduce d
(Breese an d Sontag , 1995) , an d othe r studie s sho w
that it is increased (Singh et al, 1994, 1996) . Although
the reason s for these disparat e data ar e unclear , i t is
agreed tha t (1 ) ethanol affect s circulatin g plasma an d
fetal expressio n of IGF-2 an d IGF-B P an d (2 ) ethanol
causes opposing effects o n the expressio n of these two
proteins. The reduction in IGF-1 persist s in the young
offspring (u p t o 3 weeks old), but i t abates by 40 day s
of ag e (Brees e e t al, 1993) . I n contrast , IGF- 2 an d
IGF-BP ar e unaffected in preweanling rats.
The effec t o f IGF-1 ha s been studie d in C6 gliom a
cells (e.g. , Resnicof f e t al , 1994 , 1996a , 1996b) .
These cells have the advantage of being able to proliferate
i n a serum-free medium an d i n th e absenc e o f
any priming growth factors (e.g., Isenberg et al., 1992 ;
Resnicoff e t al, 1994 ; Lu o and Miller, 1996) . IGF- 1
is a potent mitoge n fo r proliferating C6 cell s (Resni -
coff e t al., 1994 , 1996a , 1996b) . Thi s effec t i s at least
partially growt h factor-specific , a s proliferatio n o f
these cell s i s unaffected b y PDGF (Resnicof f et al. ,
1994). It is worth noting that this differential respons e
to growth factors may be a quality of the cell s becaus e
primary cultur e astrocyte s and B10 4 neuroblastoma
cells are highly regulated b y PDGF (Luo and Miller ,
1997a, 1999a ) (se e Platelet-Derive d Growt h Factor ,
above).
Ethanol inhibit s th e proliferatio n o f C 6 cell s
(Waziri e t al, 1981 ; Isenber g e t al, 1992 ; Resnicof f
et al, 1994 , 1996a , 1996b ; Luo and Miller, 1996) , and
it has been suggested that this inhibition i s mediated by
ethanol-induced disruption s of IGF-1 recepto r (IGF -
lr; Resnicof f e t al , 1994 , 1996a , 1996b) . Ethano l
blocks the mitogeni c effec t o f the ligan d (IGF-1 ) an d
interferes with receptor (IGF- 1 r) activation. Autophosphorylation
o f the IGF- 1 r is inhibited b y low concentrations
o f ethanol . Also , ethano l inhibit s th e
anti-apoptotic effect s o f IGF-1 (Gu i étal, 1997) .
Anti-mitogenie Facto r
TGFp ligand s ar e intracortica l factor s tha t tur n off
neural cel l growt h (Camero n e t al. , 1998 ; Bôttne r
et al, 2000). Exogenous TGFpl inhibit s the growth
of variou s cells , includin g C 6 cells , astrocyte s (Ro -
zovsky e t al, 1998 ; Ric h e t al. , 1999 ; Rob e e t al,
2000; Mille r an d Luo , 2002a) , B104 neuroblastoma
cells (Luo and Miller, 1999b) , and neural progenitor s
(Miller an d Luo , 2002b) . TGFp l doe s thi s b y removing
cell s fro m th e proliferativ e population, i.e. ,
reducing th e G F (Siegenthale r an d Miller , 2005b) .
Interestingly, it does not affect cel l cycle kinetics.
Transforming Growth Factor-
Mediated Signal Transduction
The effec t o f TGFpl o n cel l proliferatio n is medi -
ated throug h ER K activatio n (Fig . 11-4) . TGFp l