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

32 NORMA L DEVELOPMENT
too rich in cell adhesion proteins, neuronal migration
is impeded , possibl y because th e microenvironmen t
becomes too sticky.
Extracellular Matrix Molecule Reelin
Modern mous e genetic s hav e provide d som e muta -
tions wit h neuronal migratio n disorder s (Tabl e 3-2) .
The reeler mouse ha s received greate r attentio n fro m
developmental neurobiologist s tha n ha s an y othe r
mouse mutants . Thi s mous e exhibit s characteristi c
lamination defect s of cerebral cortex , the hippocam -
pus, and th e cerebellu m (Raki c and Caviness , 1995 ;
Lambert de Rouvroit and Goffinet, 1998) . I n the mu -
tants, neocortica l neuron s ar e generate d i n th e V Z
and S Z as in the wild-typ e animals and initiall y their
migration seems normal. A major differenc e i s that the
preplate is never split into the M Z an d th e SP ; therefore,
th e C P form s unde r the so-calle d superplate . As
the migratin g neurons approac h th e CP , neuron s i n
the reeler mic e fai l t o for m norma l architectoni c or -
ganizations. Instea d o f forming b y a n inside-ou t pattern
o f neuronogenesis , the birthdat e o f neuron s i n
the mutant cortex is reversed. Early-generated neurons
are locate d superficiall y and late-generate d neuron s
are distributed in deep cortex. Remarkably, despite the
Protein and Function
Reelin, ECM protei n
Astrotactin 1 , neuron-glia cell adhesion molecul e
Integrin a^ subunit, cell surface receptor bind s to reelin
positioning defects, neurons do make correct connections,
although the axonal pathways are distorted.
The clonin g o f th e defectiv e gen e relin ha s in -
creased interes t in thi s mutatio n (D'Arcangel o e t al. ,
1995). Reelin is expressed by Cajal-Retzius neurons i n
the M Z o f the developin g cerebral wal l (D'Arcangel o
et al., 1997) . How reelin functions in neuronal migra -
tion i s an are a o f intense research ; n o consensu s ha s
been reached. Mos t results support the idea that reeli n
controls laminatio n b y acting a s a sto p signa l fo r mi -
grating neuron s (Dulabo n e t al. , 2000) . Accordingly ,
neurons migrate past the previously deposited neurons
in the lower CP where reelin is not expressed. The mi -
grating neurons proceed t o the superficia l edg e o f the
CP borderin g the MZ where reelin i s expressed (Cur -
ran and D'Arcangelo, 1998) . This finding implies that
reelin tells the neurons to stop migrating. Some o f the
migration defects characteristic of the reeler mice, such
as th e lac k o f splitting o f th e preplate , i s rescued i n
transgenic mic e i n which reeli n expressio n is targeted
in the VZ and SZ. Thus, the role of reelin in developing
cortex is more complicated than simply providing a
migratory stop signal (Magdaleno et al., 2002).
Reelin binds to two receptors expressed by migrating
neurons , Apo E recepto r 2 and ver y low-density
lipoprotein recepto r (VLDLr ) (D'Arcangel o e t al. ,
TABLE 3- 2 Mous e mutations that affect neuronal migration
Integrin oc 6 subunit, cell surface receptor binds to laminin
Integrin (3j , cell surface receptor interacts with reelin,
laminin
Laminin Y J subunit, ECM protei n
Very low-density lipoprotei n receptor , reelin recepto r
Low-density lipoprotein receptor-related protein, reeli n
receptor also known as ApoE receptor 2
Disabled homolog 1 , interacts with VLDLr/Lrp8
Cyclin-dependent kinase 5, phosphorylates Dabi
and NUDEL
LISl/PAFAHIb, binds to dynein, microtubule
Doublecortin, microtubule-associated protein
Gene
rein
astn
itga3
itgao
itgbl
lame I
vldlr
Irp8
dabl
cdkS
PAFAHIb
dcx
Structural Phenotype
reeler mouse, inverted cortical layering , absence of
preplate split
Slowed radial migration
Abnormal laminar positioning of projection neurons
Basement membrane breac h
Cortical layering perturbation
Basement membrane breach
Cortical layerin g perturbation
Basement membrane breac h
Cortical layering perturbation
Reeler phenotype in Vldlr/LrpS doubl e knockout
Reeler phenotype in Vldlr /Lrp8 doubl e knockout
Reeler phenotype, mutated in yotari and scrambler
Inverted cortical layering
Null is lethal, hypomorphic mutations caus e
migration defect
No migration phenotyp e