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

where R is a protein and Ma n i s anchored t o Ser/Thr
residues (Takahashi et al., 2001; Yoshida et al, 2001).
The function s of POMTT, fukutin, an d Large , gen e
products o f POMTI, FCMD , an d Large, hav e no t
been determined . Bioinformatic s studies , however ,
show that eac h protei n ha s a glycosyltransferase-lik e
domain (Aravin d an d Koonin , 1999 ; Jurad o e t al. ,
1999; Peyrar d e t al. , 1999 ; Beltran-Valer o e t al ,
2002). The implicatio n is that the dystrophies and migration
defects result from abnormal protein glycosylation.
How can protein glycosylatio n enzymes regulate
neuronal migration?
Conceivably, migration involves glycosylation substrate
proteins. A candidate substrate is a-dystroglycan,
a heavily glycosylated membrane protein . The mucin -
like domain o f a-dystroglycan is heavily substituted b y
O-linked mannosy l glycan s tha t contain th e linkag e
catalyzed b y POMGnTl (Chib a e t al, 1997) . Th e
O-mannosyl glycans may play important role s in me -
diating a-dystroglyca n interaction s with lamini n (Ervasti
and Campbell, 1993 ; Smalheiser, 1993), a major
component o f th e basemen t membrane . Further ,
a-dystroglycan i n som e o f these disease s is underglycosylated
and binding to laminin is reduced (Hayash i
et aì., 2001; Holzfeind et al, 2002; Kano et al, 2002;
Michele et al., 2002). These results suggest a connection
between hypoglycosylatio n of a-dystroglycan an d
neuronal migratio n defect s i n th e brain . A n impor -
tant role for a-dystroglycan i n this process is also supported
b y finding s o f neurona l migratio n defect s i n
the brains of mice in which dystroglyean is conditionally
knocked out (Michel e et al., 2002; Moore e t al.,
2002).
Mechanisms o f overmigration may involve abrogation
o f th e PM . Th e P M i s compose d mainl y o f
laminin, collage n IV , nidogen, an d perlecan , al l o f
which regulat e cel l proliferation , migration , an d differentiation
b y interactin g wit h mainl y tw o cell sur -
face receptors: integrilis and a-dystroglycan. Th e PM ,
to which radia l glia l endfee t ar e attached , i s locate d
between th e pia mater an d the MZ . Electro n micro -
scopic analyse s show breaches i n th e P M a t site s of
ectopie neura l cluster s o f patient s wit h FCM D
(Nakano e t al. , 1996 ; Ishi i e t al, 1997 ; Sait o e t al. ,
1999). Laminin i s reduced or abnormally distribute d
in the brai n surfac e PM o f several mutant mice wit h
overmigration, includin g Lmxl a (Dreher) mic e
(Sekiguchi et al, 1994 ^ Costa et al, 2001 ) and mic e
lacking rnyristolate d alanine-rich C kinas e substrat e
(Blackshear e t al , 1997) , integri n a 6 (Georges -
NEURONAL MIGRATION 3 5
Labouesse et al, 1998) , an d integri n p] (Graus-Port a
et al , 2001) . Interestingly , integrili (3 j nul l neuron s
migrate to appropriate positions in the cerebral cortex
in chimeri c mic e (Fassle r and Meyer , 1995) , imply -
ing tha t overmigratio n i s not cause d b y a n intrinsi c
defect of the migrating neurons but b y a defective environment
i n thi s mutant . Whethe r breache s i n th e
PM ar e th e caus e o r th e resul t o f overmigration re -
mains to be clarified.
DIRECTIONAL GUIDANCE OF
NEURONAL MIGRATIO N BY
DIFFUSABLE FACTORS
LCNs o f th e olfactor y bul b (granul e cell s an d
periglomerular cells ) ar e mainl y generate d postna -
tally, during th e first 2 to 3 weeks after birt h (Altma n
and Das , 1966 ; Hinds , 1968) , althoug h som e neu -
ronogenesis continue s i n th e adul t (Corott o e t al ,
1993; Loi s an d Alvarey-Buvlla , 1994) . Retroviral -
labeling studies demonstrate tha t mos t o f the LCN s
are generate d i n th e S Z nea r th e anterio r forebrai n
(SZa) an d migrat e t o th e olfactor y bulb throug h a n
SZ pathway (Fig . 3-3 ) (Luskin , 1993 ; Zigova e t al ,
1996). Apparently , olfactory LCNs do not migrate o n
radially oriented glia l processes, a s the orientatio n o f
the radia l glia l fiber s i s orthogona l t o th e migratio n
trajectory (Kish i e t al, 1990) . Further , th e migratio n
pathway i n th e S Z i s also devoid o f axon projections
(Kishi, 1987) .
How d o olfactor y LC N migrate ? Immunohisto -
chemical studie s o f polysialic acid an d Tu J 1 expression
i n th e adul t S Z pathwa y sho w tha t migratin g
cells tend to travel in chains or streams of cells (Rousselot
et al, 1995 ; Doetsc h an d Alvarez-Buylla, 1996 ;
Jankovski and Sotelo, 1996 ; Loi s et al, 1996 ; Doetsc h
et al , 1997 ; Garcia-Verdug o e t al, 1998) . Althoug h
these chain s of migrating cells cannot b e observe d in
newborn animals because man y cells are migrating at
the same time, such chains are often observed in cul -
tures of SZ cell s plate d on collage n gel s (H u et al,
1996) or Matrigel (Wichterle et al, 1997) . Therefore ,
chain migration of olfactory LCN precursor s seems to
be mechanistically distinc t fro m radia l migration relying
on radial glia.
In vivo studies show that olfactory LCN precursor s
migrate fro m th e SZ a to the olfactory bulb in a unidirectional
manner (Luskin , 1993; Hu and Rutishauser,
1996). Thi s findin g implie s a n activ e guidanc e