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

1999; Hiesberger et al, 1999) . Mice deficient i n both
of these receptor s exhibit phenotypes identical to that
of the reeler mouse (Trommsdorff et al., 1999) . There
may b e othe r receptor s involve d in transducin g the
reelin signal . Reeli n als o binds to integri n oc 3pj an d
cadherin-related neurona l receptor s (Senzak i e t al. ,
1999; Dulabo n e t al , 2000) . Apparently , reelin -
integrin bindin g i s no t require d fo r reeli n functio n
because integrin pj knockout mouse does not exhibit
a ree/er-like phenotype.
Downstream reelin-induced signalin g involves the
phosphorylation o f Drosophila disable d homologu e
(Dab) 1 (Howell et al., 1999). Mice with mutations in
the gene s dabl, scrambler, and yotari exhibi t phenotypes
similar to that of reeler mice. Dabi binds to th e
intracellular domain s o f lipoprotein receptor s an d i s
tyrosine phosphorylate d upo n ligand-recepto r bind -
ing (Trommsdorff et al, 1998 ; Keshvar a et al., 2001).
Surprisingly, reeli n ha s been show n t o posses s a serine
protease activit y and can diges t extracellular matrix
molecules (Quattrocchi et al, 2002). Whether its
enzymatic activit y regulate s neurona l migratio n re -
mains to be evaluated.
The mous e knockou t of cyclin-dependent kinase
(Cdk) 5 (a serine/threonine kinase ) or o f its activator
protein, p35 , exhibit s a reeler-like cortica l migration
phenotype (Gilmor e e t al. , 1998 ; Kwo n an d Tsai ,
1998). A major differenc e is that th e preplat e i s split
into the MZ and the SP in these mutant mice. Thus,
Cdk5 and p35 may function in a different pathwa y to
control neurona l migratio n fro m reelin . Cdk 5 ca n
phosphorylate Dabi independent o f reelin binding to
its receptor s (Keshvara et al. , 2002) . There ma y b e
crosstalk betwee n th e reeli n signalin g pathwa y an d
the Cdk 5 pathway.
MIGRATION DEFECTS
X-linked Periventricular
Heterotopias: Failure to
Initiate Migration
X-linked periventricula r heterotopia s ar e nodule s of
neurons linin g the V Z o r SZ . Presumably there i s a
failure o f neuron s t o migrat e ou t o f proliferat i ve
zones. The geneti c defect in X-linked periventricular
heterotopia i s mutations i n FLNA , an X-linke d gen e
encoding filami n A (Fox et al., 1998) . Filami n A is a
large actin-binding phosphoprotein with a molecular
NEURONAL MIGRATION 3 3
weight of 280 kDa. It is necessary for the locomotio n
of several cell types and i s expressed by cells in all layers
o f th e developin g cerebra l cortex . Hemizygou s
males with null mutations die during the embryoni c
period. Heterozygou s female s have epileps y that ca n
be accompanie d b y othe r manifestation s suc h a s
patent ductus arteriosus. I t i s believe d tha t rando m
X-chromosome inactivatio n result s in inactivatio n o f
FLNA expressio n in strande d neurons . Recently , affected
male s with likely partial loss-of-function muta -
tions in FLNA (e.g. , amino aci d 65 6 Leu t o Phe an d
amino aci d 230 5 Tyr t o sto p codon ) hav e bee n re -
ported (Shee n e t al., 2001; Moro e t al, 2002). Interestingly,
male s wit h thes e mutation s hav e neuron s
that either migrate normally or exhibit complete mi -
gratory arrest . Thi s dichotom y suggest s tha t othe r
functionally relate d gene s can compensate fo r filamin
A deficiency . Indeed , a structurall y relate d gene ,
FLNB, i s als o expresse d i n th e developin g cerebra l
cortical wall, and both proteins can form heterodimer s
(Sheen et al., 2002).
The mechanism throug h which filamin A regulates
the initiatio n of migration is unclear. Likely it involves
the abilit y o f filami n A t o cross-lin k F-acti n int o
isotropie, orthogonal arrays (Stossel et al., 2001). Crosslinking
of F-actin increase s the viscosit y and stiffnes s
of actin an d ma y be involve d in th e initiatio n of migration.
In the V Z and SZ , FLNA i s expressed by all
cells —mitotic and postmitotic cells. If filamin A regulates
the initiation of neuronal migration, why do only
postmitotic neuron s migrat e ou t o f the V Z an d S Z
when all cells express FLNA? A potential mechanism
involves filamin A-interacting protei n (FILIP). FILIP
is expressed in the VZ and SZ, but not in postmitoti c
migrating neuron s (Nagan o et al. , 2002) . FILIP-fil -
amin A binding induces the degradation of filamin A.
Thus, the loss of FILIP expressio n in postmitotic neu -
rons may enable filami n A to control the star t of migration.
Double Cortex Syndrom e an d Type I
Lissencephaly: Prematur e Cessatio n
of Neuronal Migratio n
Double cortex describe s a conditio n i n whic h a
subcortical-band heterotopia form s i n the subcortical
IZ, the anlag e o f the whit e matter . Mutations i n a n
X-linked gene, doublecortin (dcx)y ar e a genetic caus e
of the disorder (des Portes et al, 1998 ; Gleeso n e t al,
1998). Doublecortin is a 40 kDa protein, expressed by