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

are expresse d i n the S Z of normal rodent s (Sasahara
et al, 1991 ; Yeh et al, 1991) . Th e growth-promoting
effect o f PDGF has also been described for astrocytes
(Luo an d Miller , 1999a ) an d B10 4 neuroblastom a
cells (Luo and Miller, 1997a) .
PDGF is active as a dimer, forme d as a combina -
tion o f th e tw o isoforms , PDGF- A an d PDGF-B .
PDGF-BB i s the mos t potent ligand , doubling or trebling
the growt h of B104 cells an d astrocytes , respec -
tively, over 3 days (Luo and Miller , 1997a , 1999a) . In
contrast, PDGF-A A onl y increase s cel l growt h b y
-50% (B104 neuroblastoma cells ) or -70% (astrocytes)
over the sam e period. Although the tota l length o f the
cell cycl e i s reduced, mos t o f the growt h result s fro m
the recruitment o f cells into the cyclin g population—
i.e., throug h a n increas e i n th e GF . Thi s patter n i s
reminiscent o f th e respons e o f S Z cell s t o ethano l
(Miller an d Nowakowski , 1991 ; Mille r an d Kuhn ,
1995).
The PDGF-mediate d increase in cell proliferation
is mediated throug h tw o intracellular signal transduction
cascades : the ras-raf pathwa y and th e protein kinase
C (PKC ) pathway (Fig . 11-4 ) (Lu o and Miller ,
1999a). Th e ultimat e effect s o f PDGF ar e th e tran -
sient (phasic ) activation o f mitogen-activated protei n
kinase and extracellular signal regulated kinase (ERK)
and the transcription of proliferation-associated genes .
PDGF-mediated growt h i s compromise d b y
ethanol, th e growt h amon g B10 4 cell s (Lu o an d
Miller, 1997a) and astrocytes (Luo and Miller, 1999a)
being reduced in a concentration-dependent manner .
Interestingly, the effect s o f ethanol o n the tw o ligand
isoforms are cell type-specific. The actio n of PDGF-
BB on B10 4 cells i s twice as sensitive to ethanol a s it
is to PDGF-AA (Lu o and Miller , 1997a) , an d th e in -
verse situatio n i s eviden t fo r neocortica l astrocyte s
(Luo and Miller, 1999a) . This may mean tha t PDGF
differentially affect s cel l lineage s i n vivo . Moreover ,
the variatio n i n effect s ma y underlie th e differentia l
activity o f SZ cells , whic h i n th e ra t ar e largel y neuronogenetic
prenatally and gliogenetic postnatally.
The effec t o f ethanol o n ligand-mediate d activity
apparently reflects ethanol-induced changes in recep -
tor expression and activation. Two receptors can bind
PDGF ligands : PDGF-a r an d PDGF-pr . I n B10 4
cells, ethanol target s the PDGF-ar, which ultimately
leads to a change in ERK activation (Luo and Miller,
1999a). Ethano l doe s not stop ERK phosphorylation;
rather, i t induces a sustained ER K activation, which
in turn can lead to changes in gene transcription.
ETHANOL AND PROLIFERATION OF NEURONAL PRECURSORS 18 9
Fibroblast Growth Factor-2
FGF-2 i s an importan t regulator o f cell proliferatio n
in th e V Z an d derive d zone s o f developing rodents .
An immunohistochemical study shows that FGF-2 receptors
ar e predominantl y expresse d i n V Z durin g
normal, cortical development (Weis e et al., 1993) . SZ
cells in the neonatal rat brain are also FGF-2 responsive
(Bartlet t et al, 1994 ; Gritt i et al, 1999 ; Wagne r
et al, 1999 ; Decke r e t al. , 2002) . Fo r example , in -
traperitoneal injection of FGF-2 stimulates the prolif -
eration o f neuronal precursor s in the S Z (Lachapell e
et al. , 2002) . Similarly , intraventricula r administra -
tion of FGF-2 expands the population of SZ neuronal
progenitors (Kuhn et al., 1997 ) an d increase s mitoti c
activity in the SZ and IH Z in adul t rat s (Wagne r
et al, 1999) .
FIGURE 11- 4 Signa l transductio n triggere d b y
ethanol-sensitive growt h factors . Cel l proliferatio n is
regulated b y platelet-derive d growt h facto r (PDGF )
and transforming growth factor (TGF) pi . PDGF acts
as a dime r o f A o r B isoforms . Thes e growt h factor s
bind t o specifi c trans-membran e receptor s tha t au -
tophosphorylate. Thi s proces s trigger s a cascad e o f
phosphorylation event s throug h variou s intermedi -
aries. Interestingly , although PDG F and TGFpl in -
duce opposit e effect s (mitogeni c an d anti-mitogeni c
actions, respectively) , they both stimulat e extracellular
signal-related kinase (ERK). The circle d plus and
minus sign s identif y th e action s o f ethanol . Briefly ,
ethanol ha s a specific effec t o n a single PDGF receptor
isofor m (PDGF-ar ) and , throug h bot h pro - an d
antimitogenic factors , ethanol stimulates ER K activ -
ity. This in turn can alter nuclear gene transcription.
MEK, methylethylketone ; nCAM , nerv e cel l adhe -
sion molecule; PKC, protein kinase C.