Advances in Developmental Biology and Biochem [Vol 13 - Murine Homeobox Gene Ctl] - T. Lufkin (Elsevier, 2003) WW

256 Pages·2003·3.03 MB·English

Contents

Preface
vii

List of Contributors
xi

Hox proteins and their co-factors in transcriptional regulation
1
Mark Featherstone

Msx genes in organogenesis and human disease
43
Robert E. Maxson, Mamoru Ishii and Amy Merrill

Cdx homeobox proteins in vertebral patterning
69
Martin Houle, Deborah Allan and David Lohnes

Dlx genes in craniofacial and limb morphogenesis
107
Giorgio R. Merlo, Annemiek Beverdam and Giovanni Levi

Prx, Alx, and Shox genes in craniofacial and appendicular development
133
Frits Meijlink, Sanne Kuijper, Antje Brouwer and Carla Kroon

Hox gene control of neural crest cell, pharyngeal arch and craniofacial
patterning
155
Angelo Iulianella and Paul A. Trainor

Role of Otx transcription factors in brain development
207
Antonio Simeone, Juan Pedro Martinez Barbera, Eduardo Puelles
and Dario Acampora

Colour plate section
251

Preface

It has been nearly two decades since the first homeobox gene was molecular
cloned in Drosophila. This monumental finding rapidly led to the discovery of
additional homeobox genes in essentially every animal species examined. Since
that time some twenty years ago, enormous progress has been made in our
understanding of the distribution of homeobox genes in the genomes of many
species and the common functional role homeobox genes play in cell-type
specification and development. The amino acid sequence of the homeodomain,
and
the
presence
of
other
conserved
protein
domains,
has
allowed
the
classification of homeodomain-containing proteins (homeoproteins) into over
thirty separate families (e.g. Hox, Dlx, Msx, Otx, Hmx, Cdx etc.) with most
commonly between 2–10 members per family in mammals. Additionally, recent
analysis of different animal genomes has now permitted more accurate and
detailed models of the evolution of homeobox gene families, which appear to
have expanded largely in step with overall gene number in the evolution of more
complex organisms.
With the recent completion of the sequencing of the first arthropod and
mammalian genomes a major revelation was the relative paucity of genes
necessary to construct complex animal life forms. The parsimonious nature of
genes was not so foreign to investigators in the homeobox gene area, where an
early question had always been how a single gene could fully direct the
morphogenesis and development of a complex tissue, organ or entire body
segment. This early and fundamental question on the ‘‘master’’ regulatory ability
of homeoproteins to a large part still remains a mystery, in part owing to our
limited understanding of the downstream effectors of homeobox gene function.
It would be beyond the scope of any single publication to review all recent
developments in what has been learned about homeobox gene structure, function
and expression. So here we limit ourselves to what has been learned in mammalian
systems, primarily focusing on the mouse, as the mouse remains the vertebrate
species of choice for using both forward and reverse genetic approaches to generate
either gain- or loss-of-function mutations at will. Yet, a common theme to each of
these reviews is the underlying importance of what has been learned about each
homeobox gene family in other species, particularly Drosophila, and how this has
aided our interpretation and understanding of the role these genes play in mice and
other mammals, namely human.
A question of central interest in the homeobox gene field has been how homeo-
proteins which act as DNA binding transcription factors, can with a relatively
weak specificity of DNA binding, achieve such specificity of action. The chapter by
Featherstone explores the mechanisms through which Hox and other homeoproteins
achieve specificity in their role as transcriptional regulators (both activators and

repressors) and how homeoprotein interaction with cofactors (often other
homeoproteins) affects both cooperativity and specificity of DNA binding.
Members of the msh/Msx homeobox gene family have remained remarkably
conserved during evolution relative to other homeobox gene families. The section by
Maxson et al. explores this evolutionary conservation at the functional level by
describing the role of the Msx genes in the convergence of both the control of cell
proliferation and differentiation and hence pattern via extracellular signals. This
chapter also details the role of the Msx genes in development of the mammalian skull
and goes further to integrate them into an emerging homeobox gene developmental
cascade whereby expression of the Msx genes is controlled by other homeoproteins
and the Msx proteins themselves control the expression of yet other homeobox
genes.
An example of the role of homeobox genes in patterning specific regions of the
body in a wide range of species is described in the chapter by Lohnes and colleagues
where they review what is known about the Drosophila caudal homologs in mice
(Cdx1 and Cdx2) and other species and their conserved role in patterning the
posterior end of the embryo and in gastrulation. Additional functions the Cdx1/2
genes have evolved include the control of vertebral patterning that is intertwined
with their control of the early phase of Hox gene expression. How the Cdx genes
themselves are regulated is also explored and the wingless/Wnt family of cell–cell
signaling molecules is implicated along with retinoic acid, which has also been shown
to directly regulate expression of certain members of the Hox gene complex.
The chapter by Levi and colleagues describes the role of two murine Dlx genes in
craniofacial and limb development. Homologs of Drosophila Distal-less, the murine
genes have been shown to play an evolutionary conserved role in appendage out-
growth similar to what was seen in their fly counterparts, thus further linking the
developmental programs utilized by mammalian limbs and Drosophila appendages
(antennae, labium, legs and wings). In a similar manner the chapter by Meijlink et al.
explores the contribution of the Prx, Alx and Shox genes to craniofacial and
appendicular (limb) morphogenesis. These three mammalian families are highly
similar to the Drosophila aristaless gene, which is involved in both embryonic
development and pattern formation in appendages and head segments and which
furthermore overlaps in expression with the Distal-less gene in the developing fly
head and distal tip of fly appendages.
Probably the best-characterized and most widely studied family of homeobox
genes is the Hox genes. The chapter by Iulianella and Trainor focus on the role of
Hox genes in their anterior domain of function and explore their contribution to
patterning of the cranial neural crest and head. The authors review the interplay of
multiple extracellular signaling systems in neural induction and go on to describe
how multiple regulators of Hox gene expression are now known, which include
retinoic acid and its associated nuclear receptors, Krox20, kreisler, Fgfs and Hox
proteins themselves. With regard to patterning parts of the anterior end of the
embryo in diverse species, the section by Simeone et al. review the role of the Otx
genes in murine brain development. In Drosophila the Otx homolog orthodenticle
(otd) is responsible for patterning the antennal segment, which gives rise to the eye

viii
Preface

and the antenna, as well as sections of the fly brain. This chapter also reviews what is
known about the function of neural signaling centers such as the anterior visceral
endoderm and their impact on homeobox gene expression.
Almost two decades have passed since the molecular cloning of the first
homeobox gene and during that interval great advances have been made in our
understanding of homeobox gene structure, expression, function and evolution in
mammals. At the same time many old questions remain resistant to rapid solutions,
such as a full understanding of the nature and number of different homeobox
upstream regulators (both at the DNA and protein level) how they integrate their
function with other neighboring enhancers and how they restrict themselves from
acting on genes that often lie between them and their normal homeobox responsive
gene. Likewise the issue of post-translational modification of homeoproteins and
homeoprotein cofactors (proteins or otherwise), their diversity and how they
modulate homeoprotein function are only beginning to be understood in a handful
of cases. Finally how, when and what homeoproteins control in terms of target genes
is still in its infancy. Hopefully the emergence of promising new tools in the areas of
genomics and proteomics combined with ongoing advances in molecular genetics
and bioinformatics will help us better address many of these questions in the near
future.

Preface
ix

List of Contributors

Dario Acampora
MRC Centre for Developmental Neurobiology, New Hunt’s House, 4th Floor,
King’s College London, Guy’s Campus, London Bridge, London SE1 1UL, UK
e-mail: