The Reeler Mouse as a Model of Brain Development

116 Pages·1998·4.218 MB·English

by  Catherine Lambert de Rouvroit Ph. D., André M. Goffinet M. D, Ph. D. (auth.)

Advances in Anatomy
Embryology and Cell Biology
Vol. 150
Editors
F. Beck, Melbourne D. Brown, Charlestown
B. Christ, Freiburg W. -Kriz, Heidelberg
E. Marani, Leiden R. Putz, Munchen
Y. Sano, Kyoto T. H. Schiebler, Wurzburg
K. Zilles, Dusseldorf
Springer
Berlin
Heidelberg
New York
Barcelona
Budapest
Hong Kong
London
Milan
Paris
Singapore
Tokyo
c. Lambert de Rouvroit A. M. Goffinet
The Reeler Mouse
asa Model
of Brain Development
With 30 Figures and 3 Tables
Springer
CATHERINE LAMBERT DE ROUVROIT, Ph. D.
ANDRE M. GOFFINET, M. D, PH. D.
Neurobiology Unit
University ofNamur Medical School
61, Rue de Bruxelles
5000 Namur
Belgium
ISBN-13:978-3-540-64674-7
Library of Congress-Cataloging-in-Publication-Data
Lambert de Rouvroit, C. (Catherine), 1963- . The reeler mouse as a model
of brain development / C. Lambert de Rouvroit and A.M. Goffinet. p. cm. -
(Advances in anatomy, embryology, and cellbiology, Vol. 150)
Includes bibliographical references and index.
ISBN -13:978-3-540-6467 4-7 e-ISBN -13:978-3-642-72257-8
DOl: 10.1007/978-3-642-72257-8
1. Developmental neurobiology. 2. Neurogenetics. 3. Mice-Molecular ge
netics. 4. Developmental genetics. I. Goffinet, A. II. Series QL801.E67
Vol. 150 [QP363.5] 571 s-dc21 573.8'61935]
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Preface
Only five years ago, nobody in his right mind would have consid
ered publishing a book on reeler as a model for brain develop
ment. Although this interesting mutation has been with us for
half a century, it is fair to say that, in spite of a wave ofe nthusiasm
in the late sixties and early seventies, generated primarily by
Sidman, Caviness and colleagues, studies of reeler mice fell pro
gressively out of fashion during the next two decades. All that
changed almost overnight when the cloning of the reeler gene,
dubbed reelin, was reported in Tom Curran's laboratory in 1995.
The fact that the same gene was identified at the same time
independently by two other groups using positional cloning sug
gested strongly that reelin was the right candidate. Although the
key experiments of transgenic rescue have not been made (and
perhaps will never be), the equation "reeler is reelin" has been
established beyond reasonable doubt, as alterations of the reelin
gene and/or its expression have been found in at least five alleles
of reeler and in the mutation Shaking Rat Kawasaki (SRK), an
ortholog of reeler.
During the last four years, we have witnessed a renewed inter
est in reeler and robust attacks are now mounted on various
fronts to understand better the action of reelin, to define the
modifications or variants of the protein, to characterize other
molecules interacting with reelin, either as receptors or reelin
associated proteins, and to elucidate the putative reelin signaling
pathway. Recently, several major findings were reported that
broadly extend the perspective in which work on reeler can now
be considered. First, a null mutation in the cyclin-dependent
kinase 5 (Cdk5) gene was generated by gene targeting in mice,
and displays developmental alterations in the cerebral cortex and
cerebellum that are reminiscent of those in reeler, and in fact
define a new stage of cortical development. A few months later, a
mouse deficient in the p35 protein - a non kinase activator of
Cdk5 - was also generated that replicates some features of the
Cdk5 null phenotype, particularly laminar inversion in the cor
tex. Finally, two new mutations that generate a phenocopy of
reeler, named scrambler and yotari were identified. Mice defi
cient in the mDabl gene, a probable adaptor of non-receptor
v
tyrosine kinases, similar to Drosophila disabled, have a pheno
type almost identical to reeler, and it was shown that scrambler
and yotari are indeed recessive alleles ofmDabl.
As in many other instances, this mind-boggling evolution
comes as a fitting illustration of the highly nonlinear progress of
science, characterized by alternating periods of slow work and
sudden breakthrough. Also typical of modern biology is the fact
that serendipity played a central role. Nobody could have pre
dicted that insertion of a c-fos transgene in the reelin gene would
allow the cloning of reelin, or that a mDabl knock out would
generate a reeler-like phenotype. This state of affairs is intellec
tually quite frustrating, but a healthy reminder that our theories,
particularly about the brain, are rudimentary to say the least, and
should be dealt with accordingly.
Thus far, studies of the reeler and related mouse models have
benefited our understanding of human brain malformations
mainly from a basic standpoint, by focusing our thinking on
modern biological mechanisms of development. They did not
yield any direct dividend in terms of medical output. Recent
progress in the study of some human malformations and neuro
nal migration disorders suggests that this is about to change. We
can reasonably hope that the views and theories on brain devel
opment generated from studies of mouse neurological mutations
will soon prove useful for the understanding and perhaps the
management of these debilitating diseases.
In order to try and cover most aspects of research carried out
on the reeler mouse and related models, a first chapter summa
rizes classical views on mouse brain development and reviews in
some detail brain development in reeler mice. This is followed by
a summary of current data on extracellular matrix components
in cortical development. In a second chapter, we proceed with the
genetics of reeler, including the experiments that led to the iden
tification of reelin. The genomic organization of the reelin gene
and the alterations that are found in the various reeler alleles are
described, together with the alternative splicing events that have
been defined thus far. The third chapter deals with the expression
of reelin mRNA during development, the production of anti
reelin antibodies and their use in studies of reelin protein expres
sion, as well as with some experiments, still preliminary, carried
out to define the action of the protein. A fourth chapter deals with
some comparative aspects of cortical development that point to
a possible role of reelin during brain evolution. In the last chapter,
we discuss reelin in the context of other animal mutations and
human malformations that produce related phenotypes. A pre
liminary model summarizing current data is presented.
In this small monograph, extensive - some will perhaps say
shameful-borrowing was made from works published by several
colleagues; their contribution is clearly acknowledged in the text
VI
and references. Some oft he work reviewed in the various chapters
was carried out in our laboratory and we would like to acknow
ledge particularly the contributions of I. Bar, M.e. Beckers, B.
Bernier, V. de Bergeyck, T. Huynh-Thu and I. Royaux, as well as
the expert technical assistance of C. Dernoncourt, D. Lannoy, B.
Naerhuyzen, D. Ruelle and the secretarial aid of M. De Vos.
Finally, we wish to thank Prof. E. Marani (Leiden University) for
his valuable advice and help with the final edition of the manu
script.
This review and discussion of past and recent studies of reeler
is hopefully timely, but will serve its purpose only if it fosters new
and original approaches to this old problem. Whether it succeeds
in its task is left to the appreciation of the reader.
VII
Contents
1 Brain Development in Normal and reeler Mice:
The Phenotype. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 1
1.1 Some Introductory Background . . . . . . . . . . . . . . . . . . . . .. 1
1.2 The Early Development of the Normal Cerebral Cortex.. 2
1.2.1 Orientation of Mitoses in the Ventricular Zone ... 4
1.2.2 The Preplate ................................. 6
1.2.3 The Early Marginal Zone . . . . . . . . . . . . . . . . . . . . .. 7
1.2.4 The Appearance of the Cortical Plate ............ 7
1.3 Early Cortical Histogenesis in reeler Mutant Mice ....... 8
1.4 The reeler Cerebellum .............................. 12
1.5 The reeler Inferior Olivary Complex ................. 15
1.6 The Facial Nerve Nucleus and Other Targets .......... 18
1.6.1 Other Targets of the reeler Gene ............... 20
1.7 ECM Components and Cortical Development ......... 22
1.7.1 ECM and Fiber Growth ....................... 24
1.7.2 Integrins ................................... 25
2 Genetics of reeler and Genomics of reelin ............. 27
2.1 Genetics and the Various Alleles of reeler ............. 27
2.1.1 Rat reeler-like Mutations ..................... 29
2.1.2 Other Mouse Mutations
with a reeler-like Phenotype .................. 30
2.2 Mapping of reeler and Cloning of reelin . . . . . . . . . . . . .. 30
2.2.1 Mapping................................... 30
2.2.2 The reel in cDNA ................... ; ........ 32
2.3 Genomic Organization of the reelin Gene. . . . . . . . . . . .. 34
2.3.1 Alternative Splicing of the reelin Gene ......... 34
2.3.l.l Alternative Use of a Six Base Pair Microexon .... 34
2.3.1.2 Alternative Polyadenylation .................. 35
2.3.2 The Promoter Region ........................ 36
2.3.3 Clues to the Possible Origin
of the reelin Repeats? ........................ 36
IX
3 Topography and Cellular Localization of reelin mRNA
and Protein Expression During Brain Development ... 41
3.1 reelin mRNA Expression During Development. ....... 41
3.2 Study of Reelin Protein Expression Using Antibodies
to Reelin ......................................... 49
3.2.1 Antireelin Antibodies ........................ 49
3.2.2 Reelin Protein Expression During Mouse Brain
and Human Cortical Development ............ 51
3.2.3 Studies of Reelin Function Using
Antireelin Antibodies ........................ 53
3.2.4 Is the Reelin Protein Processed
in the Embryonic Mouse Brain? ............... 54
3.3 Some Questions Raised by the Studies
of Reelin Expression ............................... 55
3.3.1 Cajal-Retzius Cells
and Other Reelin-positive Cells
in the Developing Cortical Marginal Zone ...... 55
3.3.2 Does Reelin Act on Postmigratory Neurons,
Radial Glia or Both? ......................... 56
3.3.3 Reelin Expression is Poorly Correlated
With the reeler Phenotype .................... 57
3.3.4 Reelin as a Repulsive,
Extracellular Matrix-Expanding Molecule? ..... 57
3.3.5 Reelin and Axonal Growth ................... 58
4 The reeler Mutation and Brain Evolution ............. 59
4.1 The Evolution of Brain Development: ANew Theme? .. 59
4.2 Comparative Data on Cell Migration, Maturation,
Synaptogenesis And Neurogenesis ................... 61
4.3 Comparison of Cortical Plate Development in Emys
and Lacerta. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 62
4.3.1 Biological Mechanisms Involved
in the Histogenesis of the Cortical Plate. . . . . . .. 63
4.3.2 Evolutionary Considerations ........................ 63
4.4 Reelin and a Model of Cortical Evolution. . . . . . . . . . . .. 69
5 A Model of Cortical Development Inspired by reeler:
Facts and Hypotheses. . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 73
5.1 Early Hypotheses on the Actions of the reeler Gene
on the Developing Brain. . . . . . . . . . . . . . . . . . . . . . . . . . .. 73
5.1.1 Reeler and Cell Interaction/Adhesion .......... 73
x
5.1.2 The Action of the reeler Gene is Intrinsic
to the Neuroepithelium ...................... 74
5.1.3 Reeler Phenotype and Radial Glial Fibers ....... 75
5.2 Mouse Disabledl and the Scrambler/yotari Mutations .. 76
5.3 Cydin-Dependent Protein Kinase 5
and its Activator p35: Definition of a New Step
in Mammalian Cortical Development . . . . . . . . . . . . . . .. 82
5.4 Reeler-Type Malformations
and Human Neuropathology ........................ 84
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 89
Subject Index ......................................... 107
XI