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

induces sustaine d (>9 0 min ) activatio n (Lu o an d
Miller, 1999b) , a n anti-intuitive result in that ERK is
generally associated with mitogenic activity. A recent
study of proliferating cells i n organotypi c cultures of
fetal cortex shows that cycling cells in the VZ respond
to TGFpl (Siegenthale r an d Miller , ZOOSb) . As with
the dissociated cells, TGFpl inhibits VZ cell proliferation
in situ by increasing the exit of cells from the cycling
populatio n an d concomitantl y decreasin g
the GF.
Combined treatmen t o f cortica l slice s wit h
ethanol and TGFp 1 affects the expressio n of cell cycle-related
proteins (Siegenthale r an d Miller, 20 0 5b) .
For example , tota l cycli n D l expressio n i s reduce d
in th e VZ, an d becaus e ethano l an d TGFpl d o no t
affect th e frequenc y o f cyclin Dl-positive cells , i t ap -
pears tha t th e amoun t o f cycli n D l pe r cel l i s reduced.
A simila r decremen t i n p2 7 expressio n ha s
been detected . A s for p21, co-treatment with ethano l
and TGFp l eliminate d th e increas e i n p2 1 expression
promoted b y TGFpl alone. Thus, three proteins
involved in the transition o f cells from Gl (t o either S
or GO ) ar e depresse d b y combine d exposur e t o
ethanol and TGFpl. It appears that ethanol interferes
with TGFpl regulation o f cell cycle activity.
In Vivo Transforming Growth
Factor Systems
Various immunohistochemica l analyse s hav e show n
that th e developin g nervou s system contains a n en -
dogenous TGFp system (Flanders et al., 1991 ; Pelto n
et al, 1991 ; Miller , 2003b) . TGF p ligand s ar e expressed
i n th e V Z an d S Z o f th e cerebra l vesicl e
in vivo (Fig . 11-5) . TGFpl i s expressed i n th e V Z
pre- an d postnatall y and TGFp2 i s expressed during
the first postnata l week . Potentiall y mor e importan t
than ligan d expressio n i s the distributio n o f the tw o
chief TGF P receptors , TGFpI r an d TGFpIIr . Th e
TGFpIr is expressed in both neocortica l proliferativ e
zones throughou t life , wherea s th e TGFpII r i s only
expressed i n th e VZ . Moreover , bot h TGFp 2 an d
TGFpIr are expressed by radial glia.
Prenatal exposur e to ethano l affect s endogenou s
TGFP syste m expressio n i n viv o (Miller , 2003b) .
TGFpl expression falls in immature and mature rats,
whereas TGFp 2 expressio n rise s onl y i n perinates .
Changes i n recepto r expressio n are mos t eviden t for
the TGFpIr ; it s expression i s significantly highe r i n
ethanol-treated rats, regardless o f age. These ethanol -
ETHANOL AND PROLIFERATION OF NEURONAL PRECURSORS 19 1
FIGURE 11- 5 Transformin g growth facto r (TGF ) P
ligands an d receptor s i n th e developin g ventricula r
and subventricula r zones . Pair s of images depict th e
distribution o f immunolabeling for TGFpl (to p left) ,
TGFp2 (to p right), TGFpIr (botto m left) , an d TGF -
pIIr (bottom right ) in control (Ct) and ethanol-treate d
(Et) perinates . Ethano l markedl y affect s ligan d an d
TGFpIIr expressio n in the subventricula r zone (SZ) .
Open and solid arrows identify immunolabeling i n the
ventricular zone (VZ ) and SZ, respectively. Curved arrows
labe l radia l gli a i n th e intermediate zon e (IZ) .
Scale bars =100 jlm. (Source; Images taken, with permission,
fro m Mille r (2003b) , J Com p Neuro l
460:410-424.)
induced change s ar e associate d wit h alteration s i n
the distributio n o f cell s tha t ar e TGFpl , TGFp2 ,
TGFpIr, an d TGFpII r immunoreactive . Th e mos t
marked change s ar e increase s i n S Z expressio n o f
TGFp ligands an d especiall y receptors . Thi s finding
may underli e th e increas e i n gliosi s that occur s fol -
lowing early postnatal ethanol exposure (Fletcher an d
Shain, 1993 ; Goodlett et al, 1993) .
Lineage Specificity
Studies o f th e effect s o f exogenou s TGFp l impl y
that the endogenous TGFp system in the developin g
and/or adul t brain i s affected b y ethanol. In general ,