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

34 NORMA L DEVELOPMENT
migrating an d man y differentiatin g neurons. I t i s a
microtubule-associated protei n wit h n o know n ho -
mology wit h othe r microtubule-associate d protein s
(Francis et al., 1999; Gleeson e t al., 1999 ; Hores h et al.,
1999). Doublecorti n stimulate s microtubule polymer -
ization b y binding t o 1 3 protofilament microtubule s
(Moores e t al., 2004). It is principally localized i n th e
leading processe s o f migratin g neuron s (Friocour t
et al., 2003). Thus, doublecortin may promote move -
ment by inducing microtubule polymerizatio n i n the
leading processes of migrating neurons.
Classical lissencephal y (type I ) i s a brai n malfor -
mation characterize d b y absent o r reduce d gyratio n
and a cortex that is thicker and has a rudimentary four
layers. I t is associated with severe mental retardation ,
epilepsy, an d cerebra l palsy . Mos t case s ar e du e t o
mutations o f lisi, encoding LIS I or platelet-activatin g
factor acetylhydrolas e isofor m I b (PAFAHIb , a non -
catalytic subunit o f the enzyme ) (Reine r e t al., 1993 ;
Hattori et al., 1994). Besides being part of an enzyme ,
LISl/PAFAHIb ha s a nonenzymati c function . Th e
homolog i n fungu s Aspergillus i s NudF, a n essentia l
part of a signaling pathway that regulate s nuclea r mi -
gration (Wynshaw-Bori s an d Gambello , 2001) . Evi -
dence indicate s that LISl/PAFAHIb regulates nuclear
movement b y an evolutionary-conserve d mechanis m
similar to that of the fungus. It binds to and regulate s
the function an d distributio n of dynein (mammalia n
NudA homolog) , whic h function s a s a minu s end -
directed microtubule-associate d moto r protein . Thus ,
LISl/PAFAHIb ma y be par t o f the protei n comple x
that exert s force s o n th e microtubule s surroundin g
the nucleu s i n migratin g neuron s an d pullin g th e
nucleus into the leading process (Tanaka et al., 2004).
A role for LISl/PAFAHIb in nuclea r translocatio n is
also supported b y its binding t o two other dynein in -
teracting proteins , NUDE L an d mNUD E (mam -
malian Nud E homologs ) (Fen g e t al. , 2000 ; Lian g
et al, 2004). NUDEL and mNUDE colocalize a t the
centromere tha t migrate s ahea d o f the nucleus . Th e
distance betwee n th e centromer e an d th e nucleu s
is enlarge d i n LISl/PAFAHIb-deficien t neuron s
(Tanaka e t al, 2004). Thus, LISl/PAFAHIb play s an
important rol e i n nuclea r translocatio n durin g neu -
ronal migration.
Type II Lissencephaly: Overmigration
Several form s o f congenita l muscula r dystrophies —
Walker-Warburg syndrome (WWS) , muscle-eye-brain
disease (MEB) , an d Fukuyama-typ e congenita l
muscular dystroph y (FCMD ) —are associate d wit h
cortical dysplasia . These are autosomal recessiv e dis -
orders characterize d b y congenita l muscula r dystro -
phy, ocula r abnormalities , an d cortica l dysplasi a
(Santavuori e t al., 1989) . Magneti c resonanc e imag -
ing of MEB patient s reveal s hydrocephalus associate d
with polymicrogyra or pachygyra caused by ectopie lo -
cation o f neura l tissue s i n th e leptomeninges , als o
known a s cobbleston e complexe s o r typ e I I
lissencephaly (Valann e et al. , 1994 ; Corman d e t al. ,
2001). Presumably , thes e abnormalitie s result whe n
the neurons migrat e to o far, passing through th e MZ ,
the glial-limiting membrane, the piai basement mem -
brane (PM), and the pia (Ross and Walsh, 2001).
Each o f the congenita l muscula r dystrophie s ha s
been associate d wit h mutatio n o f a spécifi e gene .
In WWS , mutation s ar e i n th e gene s codin g fo r
protein-O-mannosyl transferase s (POMT 1 an d
POMT2) (Beltran-Valer o e t al, 2002 ; va n Reeuwij k
et al. , 2005) . Th e defectiv e gen e fo r ME B map s t o
chromosome lp32-3 4 (Corman d e t al. , 1999) , an d
the mutated gen e is POMGnTl. Peopl e wit h FCMD
have a retrotransposon insertio n int o the 3 ' untranslated
regio n o f FCMD . Thi s insertio n result s i n a
dramatic reductio n i n FCMD expression .
The myodystroph y (myd) mous e ha s muscle , eye ,
and neurona l migratio n defects in the brain similar to
those i n humans with congenital muscula r dystrophie s
(Holzfeind e t al., 2002). This myd mouse ha s muscle ,
eye, an d brai n defect s associate d wit h overmigratio n
(Holzfeind et al, 2002). In the myd mouse, the genetic
defect i s a functional deletio n i n the Large gene (likeacetylglucosaminyltransferase)
(Grewa l e t al. , 2001) .
The my d mutation is now designated Large m y d . I n hu -
mans, mutation s i n Large gene cause congenita l mus -
cular dystroph y MDC1 D (Longman , e t al , 2003 )
Thus, four ne w genes, POMT1, POMGnTl, FCMD,
and Large, have bee n associate d wit h congenital mus -
cular dystrophies , an d eac h cause s simila r overmigra -
tion defects when mutated .
The functio n of POMGnTl ha s been describe d in
vitro. POMGnTl encode s a n enzym e involve d i n
O-mannosyl glycosylatio n o f protein s calle d UDP -
N-acetylglucosamine: protein-O-mannos e p-l,2-N -
acetylglucosaminyl transferas e (POMGnTl), Th e
enzyme catalyze s the following reaction:
UDP-GlcNAc + Man-R
-> GlcNAc(31-2Man-R + UDP