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

36 NORMA L DEVELOPMENT
FIGURE 3- 3 Tangentia l migratio n o f olfactor y loca l
circuit neuron s (LCNs) . A parasagitta l sectio n
through th e middl e of the olfactor y bulb (OB) of the
forebrain o f the mous e is shown. Olfactory LCNs ar e
generated i n the anterior subventricular zone (SVZa ;
shown betwee n arrows) . The y migrat e t o th e O B
within the SVZa (show n in dotted areas) . After arriving
in the bulb, they migrate i n a radial fashion to reach
their fina l location s i n th e granul e cel l laye r an d
glomerular layer . The septu m i s locate d media l t o
this section . CC , corpu s callosum ; CP , caudoputa -
men; CTX , cerebra l cortex ; fmi , forceps mino r cor -
pus callosum.
mechanism. Th e olfactor y bul b ma y secret e a
chemoattractant(s) (Li u an d Rao , 2003) . Further -
more, th e cauda l part s o f th e septu m an d th e
choroid plexus, which lie behind the migratio n pathway,
secret e a chernorepulsiv e factor(s ) (H u an d
Rutishauser, 1996) . Th e chernorepulsiv e activity secreted
from th e septum is a member of the Sli t family
of protein s (Siiti , SlitZ , an d Slit3 ) (Hu , 1999 ; W u
et al., 1999) . Slit , first discovered i n Drosophila, an d
also found in mammals, regulates the growth of axons
crossing a t th e midlin e (Ba-Charve t e t al. , 1999 ; L i
et al. , 1999 ) b y interacting with roundabout (Robo)
receptors (Kidd et al, 1998). Robo receptors are members
of the immunoglobulin superfamily of transmembrane
molecule s (Zalle n e t al. , 1998 ; Kid d e t al. ,
1999). Th e Slit/Rob o repulsive signal i s mediated i n
part by the proteins enable d an d abelson, Rh o famil y
guanidine triphospotase s (GTPases) , an d Slit-Rob o
GTPase activatin g proteins (srGAPs) (Bashaw et al. ,
2000; Wong et al, 2001).
Soluble factor s ma y als o b e involve d i n activ e
guidance i n th e migratio n o f cortical neurons . Thi s
conclusion i s supported b y studies of LCN migratio n
from the GE to the cerebral cortex. In vitro, these migrating
neurons are repelled b y the Sli t proteins that
are expresse d b y th e G E (Zh u e t al. , 1999 ) an d at -
tracted by substances released by the developing cortex
(Marin e t al. , 2003 ; Wichterl e e t al , 2003) . Neuropilins
are transmembrane receptor s that mediate th e
repulsive guidance activitie s o f class 3 semaphorins.
Neuropilin 1 and 2 are expresse d by the LCN s tha t
migrate from th e GE t o cerebral cortex (Marin et al.,
2001). Neuropili n knockou t mic e hav e decrease d
numbers of LCNs in neocortex.
Successful navigatio n o f neurons involve s mor e
than attraction and repulsion. While en route within
the SZ a pathway , olfactor y LCN s d o no t deviat e
from thei r rout e int o surroundin g regions (Luskin ,
1993). What confines the cell s to the SZ a pathway?
The S Z migration pathway in adult mice is rich in astrocytes,
tenascin, and chondroiti n sulfat e proteogly -
can (Thomas et al., 1996). Thus, it is possible that the
migrating cell s migh t hav e stronge r affinit y fo r th e
SZ, becaus e th e S Z contain s differen t extracellula r
matrix molecule s an d cel l type s fro m thos e i n sur -
rounding regions.
SUMMARY AND CONCLUSION S
Neuronal migration is a complex phenomenon regu -
lated b y man y factors . I n vitr o perturbatio n studies
and molecula r studie s in bot h th e mous e an d hu -
mans identify som e key molecules that are involved.
Examples includ e factor s extrinsic an d intrinsi c to a
migrating neuron . Thes e extrinsi c factors , suc h a s
soluble an d extracellula r matri x molecule s (neu -
rotrophins, reelin , an d Slit) , an d intrinsi c factors,
such a s cytoskeletal proteins (filamin , doublecortin ,
and PAFAHIb) , work in concert. They likely interact
with cel l surfac e receptor s an d signalin g pathways.
Some o f th e mechanism s ar e jus t beginnin g t o
emerge. I n addition , ther e ar e critica l interaction s
between geneti c an d environmenta l o r epigeneti c
factors.
Astn astrotacti n
Abbreviations
BDNF brain-derive d neurotrophic factor
Cdk cyc l in-dependent kinase
CP cortica l plate
Dab disable d
EGFr epiderma l growth factor recepto r