Download Elke Winterhager (Ed.) Gap Junctions in Development

Elke Winterhager (Ed.)
Gap Junctions in Development and Disease
Elke Winterhager (Ed.)
Gap Junctions in
Development
and Disease
With 47 Figures, 10 in Color
123
Professor Dr. Elke Winterhager
Medical Faculty of the
University Duisburg-Essen
Hufelandstr. 55
45122 Essen
Germany
e-mail: [email protected]
Library of Congress Control Number: 2005926503
ISBN-10 3-540-26156-7 Springer-Verlag Berlin Heidelberg New York
ISBN-13 978-3-540-26156-8 Springer-Verlag Berlin Heidelberg New York
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Preface
These are challenging times for scientists characterizing signaling pathways of their special interest, because the techniques employed to analyze
molecular functions or interactions have developed rapidly in recent years.
With regard to gap junctions, molecular cloning of the different connexin
isoforms, sequencing of several vertebrate genomes, generation of mice
carrying mutations of the different connexin genes, and targeting of inherited human diseases to mutated connexin genes have given completely new
insights into this research field. The use of modern techniques has contributed to specifying and broadening our knowledge of these intercellular
channels. However, at the same time, more sophisticated new questions
have arisen. Just to mention some milestones in the history of gap junction research: this special cell–cell contact was identified as an intercellular
nexus between adjacent cells by Dewey and Barr in 1962 and further characterization of the structure of this intercellular channel in the following
years led to the well-known structure of the two hemichannels, each composed of six connexin subunits which form a water-filled pore for the
exchange of molecules. The gap-junction world became complicated with
the identification of different connexin proteins, starting with the cloning
of connexin32 by David Paul in 1986 and hopefully ending with all the
known 20 members in the human and 21 members in the mouse genome.
Furthermore, the existence of at least 20 different channels in humans with
different electrophysiological properties has been shown by evidence that
the channels can be composed of different connexin isoforms, leading to
modifications of their channel properties.
The divergency of the channels has evoked the question of whether these
channels form a redundant system, or are highly specific in mediating signal
cascades. To answer this question numerous connexin knockout mice have
been established, starting with the connexin43 knockout mouse by Reaume
et al. in 1995 with the unexpected result of a special heart defect.
The specific function of the connexins in development and organ function has been evaluated by systemically knocking out the different connexins and the replacement of one connexin by another isoform, which is
reviewed in the first chapter by Klaus Willecke. Since the gap junctions are
indeed channels responsible for ion transport across adjacent cell borders
and the propagation of membrane electricity and Ca2+ waves, an inten-
VI
Preface
sive field of gap-junction physiology has developed, defining the different
channel properties. However, up to now, it remains an open question as to
what types of molecules in what amounts are crossing this channel. The
regulation of discrimination between the molecules which could pass with
limitations through these channel pores is still under discussions. It has
always been puzzling that the channel properties exclusively could govern the specific tissue functions found in the different mouse mutants. In
particular, the hypothesis already postulated by Loewenstein in the 1960s,
stating that these channels are involved in growth control and thus responsible for tumorigenesis, never really fit the known channel properties.
Meanwhile, it has become evident that several connexin functions could
be mediated via protein–protein interactions at the C-terminus of the connexin. Thus, there is a need to discriminate between channel and protein
function. Impairment of development and diseases need not be based on
connexin mutations, but rather on wrong signaling mediated via protein–
protein interactions at the C-terminus. Research on gap junctions gained
much more social respect when it became obvious with the publication of
Bergoffen et al. (1993) that connexin32 mutations are responsible for the
X-linked Charcot Marie tooth disease. This discovery was followed by discoveries of several other connexin mutations which lead to specific diseases
in humans. The most important ones are described here in this volume.
In the meantime, it has become impossible to cover all aspects of connexin research. In this volume, we have focused on the role of connexin
channels in embryonic development and in the development of human
diseases.
This volume deals with connexin channel redundancy, specificity, cell
signaling, and conductivity, which are responsible for developmental processes and appropriate organ function. Although these contributions cannot completely answer the question why the loss or mutation in gapjunction proteins leads to a specific phenotype, at least they describe the
direction of gap-junction research and how research will proceed in future.
I would like to express my profound thanks to all the authors who
contributed the various chapters on their special topics. They did a great
job and it was a joy to collaborate with my colleagues while editing this
book.
Elke Winterhager
Essen, February 2005
Contents
1 Connexin and Pannexin Genes in the Mouse and Human Genome 1
Klaus Willecke, Jürgen Eiberger, Julia von Maltzahn
1.1 Introduction .................................................................. 1
1.2 Connexin Genes ............................................................. 5
1.3 Pannexin genes .............................................................. 9
1.4 Outlook......................................................................... 10
References ............................................................................. 11
2 Essential Role of Gap Junctions
During Development and Regeneration of Skeletal Muscle
Julia von Maltzahn, Klaus Willecke
2.1 Introduction ..................................................................
2.2 Development of Skeletal Muscles.......................................
2.2.1 Embryonic Origin of Myoblasts ...............................
2.2.2 Myotube Formation by Myoblast Fusion ...................
2.2.3 Characteristics of Primary and Secondary Myotubes ..
2.2.4 Gap Junctional Intercellular Coupling
During Myogenesis ................................................
2.2.5 Connexin Expression During Fusion of Myoblasts ......
2.2.6 Connexin Expression in Myotubes ...........................
2.3 Regeneration of Adult Skeletal Muscles ..............................
2.3.1 Satellite Cells ........................................................
2.3.2 Connexin Expression During Muscle Regeneration ....
References .............................................................................
3 Connexins in Cardiac Development:
Expression, Role, and Transcriptional Control
Daniel B. Gros, Sébastien Alcoléa, Laurent Dupays, Sonia Meysen,
Magali Théveniau-Ruissy,
Birgit E.J. Teunissen, Marti F.A. Bierhuizen
3.1 Introduction ..................................................................
3.2 Multiple Connexin Genes Are Expressed in the Heart...........
3.2.1 The Cardiac Connexins ..........................................
13
13
13
13
15
16
16
17
19
21
22
24
25
29
29
30
30
VIII
Contents
3.2.2 Expression Patterns of Cardiomyocyte-Related Cx43,
-40 and -45 in the Adult Mouse Heart .......................
3.2.3 Spatiotemporal Expression Patterns
of Cardiomyocyte-Related Cx43, -40 and -45
in the Developing Mouse Heart................................
3.3 Role of Cxs in Heart Development .....................................
3.3.1 No Intrinsic Cardiomyocyte-Autonomous
Requirement for Cx43 During Heart Development .....
3.3.2 Cx40 is Involved in the Septation Process ..................
3.3.3 Cx45 is Required for the Normal Progress
of Cardiogenesis ....................................................
3.4 Transcriptional Control of Cardiomyocyte-Related Cxs ........
3.4.1 Structure and Regulation of the Cx43 Gene ...............
3.4.2 Structure and Regulation of the Cx40 Gene ...............
3.4.3 Structure of the Cx45 Gene .....................................
3.5 Conclusions ...................................................................
References .............................................................................
4 Gap Junction and Connexin Remodeling in Human Heart Disease
Nicholas J. Severs, Emmanuel Dupont, Riyaz Kaba, Neil Thomas
4.1 Introduction ..................................................................
4.2 Gap Junctions and Connexins in Cardiomyocytes
of the Normal Heart ........................................................
4.3 Alterations in Gap Junctions and Connexin Expression
in Heart Disease .............................................................
4.4 Ventricular Myocardium in Disease ...................................
4.4.1 Structural Remodeling ...........................................
4.4.2 Remodeling of Connexin43 Expression .....................
4.4.3 Remodeling of Expression of Connexin45
and Connexin40 ....................................................
4.5 Short-Term Effects of Ischemia .........................................
4.6 Remodeling of Gap Junctions and Connexin Expression
in Diseased Atrial Myocardium .........................................
4.7 Significance of Connexin Co-Expression: New Tools ............
4.8 Concluding Comment .....................................................
References .............................................................................
32
34
38
38
39
40
41
42
45
49
50
50
57
57
58
61
62
62
64
68
69
70
72
76
76
5 Gap Junction Expression in Brain Tissues
with Focus on Development
83
Rolf Dermietzel, Carola Meier
5.1 Gap Junctions and Neurogenesis: Some Basic Aspects .......... 83
Contents
IX
5.2
Segregation of Connexin Expression
During Brain Development .............................................. 88
5.2.1 Prenatal Expression ............................................... 88
5.2.2 Postnatal Expression .............................................. 90
5.3 Drawing a General Scheme of Gap Junction Function
in the Developing Brain ................................................... 92
5.4 Pitfalls in Defining Cell-Specific Expression of Connexins
in Brain Tissues .............................................................. 94
5.5 Segregation of Connexins During Glial Lineaging ................ 95
5.5.1 The Oligodendrocytic Lineage................................. 95
5.5.2 The Astrocytic Lineage ........................................... 98
5.6 Upstream Events Regulating Connexin Expression .............. 100
References ............................................................................. 102
6 Connexins Responsible for Hereditary Deafness –
The Tale Unfolds
111
Martine Cohen-Salmon, Francisco J. del Castillo, Christine Petit
6.1 Introduction .................................................................. 111
6.2 Connexin Genes and Hearing Impairment.......................... 112
6.2.1 CX26 (GJB2)
and Autosomal Recessive Deafness DFNB1................ 112
6.2.2 CX26 (GJB2)
and Autosomal Dominant Deafness DFNA3............... 118
6.2.3 CX30 (GJB6)
and Autosomal Dominant Deafness DFNA3’.............. 119
6.2.4 Other Connexin Genes and Deafness ........................ 120
6.3 Inner Ear and Gap Junctions ............................................ 122
6.3.1 Inner Ear Architecture ........................................... 122
6.3.2 Connexin Expression in the Cochlea ........................ 124
6.3.3 Gap Junctions and Inner Ear Homeostasis................. 125
6.4 Future Prospects............................................................. 128
References ............................................................................. 128
7 Human Connexins in Skin Development and Skin Disorders
135
Gabriele Richard
7.1 Introduction .................................................................. 135
7.2 The Gap Junction System of Human Skin ........................... 136
7.2.1 Changing Patterns of Connexin Expression
During Human Skin Development ........................... 136
7.2.2 Connexin Expression
in the Mature Human Epidermis.............................. 139
X
Contents
7.2.3 Changes in Connexin Expression
During Epidermal Differentiation ............................ 140
7.3 Connexin Disorders of the Skin ........................................ 142
7.3.1 Erythrokeratodermia Variabilis ............................... 146
7.3.2 Palmoplantar Keratodermas.................................... 151
7.3.3 Ectodermal Dysplasias ........................................... 156
7.4 Summary....................................................................... 163
References ............................................................................. 164
8 Intercellular Communication in Lens Development and Disease 173
Adam M. DeRosa, Francisco J. Martinez-Wittinghan,
Richard T. Mathias, Thomas W. White
8.1 Introduction .................................................................. 173
8.2 Connexin Specialization in the Lens .................................. 175
8.3 Genetic Manipulation of Lens Connexins ........................... 177
8.3.1 Knockout of Cx43 .................................................. 177
8.3.2 Knockout of Cx46 .................................................. 179
8.3.3 Knockout of Cx50 .................................................. 180
8.3.4 Knockin of Cx46 into the Cx50 Gene ........................ 181
8.4 How Does Cx46 Prevent Cataract? ..................................... 185
8.5 How Does Cx50 Influence Lens Growth? ............................. 188
8.6 Human Connexin Mutations Cause Cataract ....................... 190
References ............................................................................. 191
9 Connexin Modulators of Endocrine Function
197
Philippe Klee, Nathalie Boucard, Dorothée Caille, José Cancela,
Anne Charollais, Eric Charpantier, Laetitia Michon,
Céline Populaire, Manon Peyrou, Rachel Nlend Nlend,
Laurence Zulianello, Jacques-Antoine Haefliger, Paolo Meda
9.1 Introduction .................................................................. 197
9.2 Endocrine Cells Are Connected by Selected Connexins ........ 199
9.3 Different Endocrine Cells
Express Different Connexin Patterns ................................. 201
9.3.1 Cells Producing Peptide Hormones .......................... 201
9.3.2 Cells Producing Glycoprotein Hormones................... 207
9.3.3 Cells Producing Steroid Hormones........................... 207
9.3.4 Cells Producing Catecholamines .............................. 208
9.3.5 Cells Producing Pheromones................................... 209
9.4 Some Endocrine Cells Share Connexins with Their Targets ... 209
9.5 Nonsecretory Functions of Connexins in Endocrine Glands .. 210
9.6 Hormones and Connexins................................................ 212
9.7 The Future ..................................................................... 213
References ............................................................................. 215
Contents
XI
10 Roles of Gap Junctions in Ovarian Folliculogenesis:
Implications for Female Infertility
223
Gerald M. Kidder
10.1 Introduction .................................................................. 223
10.2 Ovarian Follicle Development........................................... 224
10.3 Connexins in Developing Follicles ..................................... 225
10.4 Roles of Individual Connexins in Folliculogenesis................ 228
10.5 Connexin Redundancy in Ovarian Follicles ........................ 232
10.6 Implications for Understanding Human Female Infertility .... 233
10.7 Conclusions ................................................................... 234
References ............................................................................. 235
11 Placental Connexins of Mice and Men
239
Caroline Dunk, Mark Kibschull, Alexandra Gellhaus,
Elke Winterhager, Stephen Lye
11.1 Introduction .................................................................. 239
11.1.1 Temporal and Spatial Pattern of Connexins
in Placentae of Mice and Men .................................. 241
11.2 The Role of Gap Junction Connexins in the Murine Placenta . 241
11.2.1 Connexin 26 Facilitates Transport
Across the Placental Barrier .................................... 242
11.2.2 Connexin 31 Regulates Murine Trophoblast
Cell Lineage Development....................................... 243
11.2.3 TS Cells as a Model to Investigate the Role
of Connexins in Placental Development .................... 244
11.3 The Role of Gap Junction Connexins in the Human Placenta . 246
11.3.1 Cx43 Supports Villous Cytotrophoblast Fusion
to Form Syncytium ................................................ 246
11.3.2 A Novel Role for Cx43 in Intracellular Signaling ......... 247
11.3.3 Connexin 40 Regulates Human Trophoblast
Extravillous Cell Lineage Development ..................... 248
11.4 Analogous Functions of Murine and Human Connexins
in Placental Development................................................. 250
References ............................................................................. 251
12 Connexins in Growth Control and Cancer
253
Christian C. Naus, Gary S. Goldberg, Wun Chey Sin
12.1 Introduction .................................................................. 253
12.2 Connexins and Gap Junctions ........................................... 255
12.3 Gap Junctions and Tumor Suppression............................... 255
12.3.1 Endogenous Expression of Connexins in Tumors ....... 255
12.3.2 Regulation of Endogenous Connexin Expression........ 256
XII
Contents
12.3.3 Gap Junctions and Oncogenic Transformation ........... 257
12.3.4 Direct Effects of Altering Connexin Gene Expression .. 259
12.4 Mechanisms of Connexin-Mediated Growth Suppression...... 259
12.4.1 Junction-Mediated Growth Suppression .................... 260
12.4.2 Nonjunctional Functions ........................................ 261
12.4.3 Connexin-Interacting Proteins ................................ 262
12.4.4 Direct Interaction of Cx43 with CCN3,
a Growth Suppressor .............................................. 264
12.5 Conclusions ................................................................... 265
References ............................................................................. 266
Subject Index
275
Contributors
Alcoléa, S.
Laboratoire de Génétique et Physiologie du Développement (UMR CNRS
6545), Institut de Biologie du Développement de Marseille (IBDM, IFR 15),
Université de la Méditerranée, Marseille, France
Bierhuizen, M.F.A.
Department of Medical Physiology, University Medical Center, Utrecht, The
Netherlands
Boucard, N.
Department of Cell Physiology and Metabolism, University of Geneva,
Medical School, 1211 Genève 4, Switzerland
Caille, D.
Department of Cell Physiology and Metabolism, University of Geneva,
Medical School, 1211 Genève 4, Switzerland
Cancela, J.
Department of Cell Physiology and Metabolism, University of Geneva,
Medical School, 1211 Genève 4, Switzerland
Charollais, A.
Department of Cell Physiology and Metabolism, University of Geneva,
Medical School, 1211 Genève 4, Switzerland
Charpantier, E.
Department of Cell Physiology and Metabolism, University of Geneva,
Medical School, 1211 Genève 4, Switzerland
Chey Sin, W.
Department of Cellular and Physiological Sciences, The University of British
Columbia, Vancouver, BC, Canada V6R 1W9
Cohen-Salmon M. (e-mail: [email protected])
INSERM U587, Unité de Génétique des Déficits Sensoriels, Institut Pasteur,
25, rue du Dr Roux. 75724 Paris Cedex 15, France
XIV
Contributors
DeRosa A.M. (e-mail: [email protected])
Program in Genetics, State University of New York, Stony Brook, New York
11794–8661, USA
del Castillo, F.J.
INSERM U587, Unité de Génétique des Déficits Sensoriels, Institut Pasteur,
25, rue du Dr Roux. 75724 Paris Cedex 15, France
Dermietzel, R. (e-mail: [email protected])
Department of Neuroanatomy and Molecular Brain Research, Ruhr-University Bochum, Universitätsstrasse 150, 44801 Bochum, Germany
Dunk, C.
Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto,
Canada
Dupays, L.
Laboratoire de Génétique et Physiologie du Développement (UMR CNRS
6545), Institut de Biologie du Développement de Marseille (IBDM, IFR 15),
Université de la Méditerranée, Marseille, France
Dupont, E.
National Heart and Lung Institute, Imperial College London, London, UK
Eiberger, J.
Institut für Genetik, Abt. Molekulargenetik, Römerstr. 164, 53117 Bonn,
Germany
Gellhaus, A.
Institute of Anatomy, University of Essen, Essen, Germany
Goldberg, G.S.
Department of Molecular Biology, University of Medicine and Dentistry of
New Jersey, Stratford, New Jersey 08084, USA
Gros, D.B. (e-mail: [email protected])
Laboratoire de Génétique et Physiologie du Développement (UMR CNRS
6545), Institut de Biologie du Développement de Marseille (IBDM, IFR 15),
Université de la Méditerranée, Marseille, France
Haefliger, J.A.
Department of Internal Medicine, University of Lausanne, Medical School,
1011 Lausanne, Switzerland
Contributors
XV
Kaba, R.
National Heart and Lung Institute, Imperial College London, UK
Kibschull, M.
Institute of Anatomy, University of Essen, Essen, Germany
Kidder, G.M. (e-mail: [email protected])
Department of Physiology and Pharmacology, The University of Western
Ontario, London, Ontario N6A 5C1, Canada
Klee, P.
Department of Cell Physiology and Metabolism, University of Geneva,
Medical School, 1211 Genève 4, Switzerland
Lye, S. (e-mail: [email protected])
Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University
Avenue, Toronto, Ontario M5G 1X5, Canada
Maltzahn, J. von
Institut für Genetik, Abt. Molekulargenetik, Römerstr. 164, 53117 Bonn,
Germany
Martinez-Wittinghan, F.J.
Department of Physiology and Biophysics, State University of New York,
Stony Brook, New York 11794–8661, USA
Mathias, R.T.
Department of Physiology and Biophysics, State University of New York,
Stony Brook, New York 11794–8661, USA
Meda, P. (e-mail: [email protected])
Department of Cell Physiology and Metabolism, University of Geneva,
C.M.U., 1 rue Michel Servet, 1211 Geneva 4, Switzerland
Meier, C.
Department of Neuroanatomy and Molecular Brain Research, Ruhr-University Bochum, Universitätsstrasse 150, 44801 Bochum, Germany
Meysen, S.
Laboratoire de Génétique et Physiologie du Développement (UMR CNRS
6545), Institut de Biologie du Développement de Marseille (IBDM, IFR 15),
Université de la Méditerranée, Marseille, France
XVI
Contributors
Michon, L.
Department of Cell Physiology and Metabolism, University of Geneva,
Medical School, 1211 Genève 4, Switzerland
Miquerol, L.
Laboratoire de Génétique et Physiologie du Développement (UMR CNRS
6545), Institut de Biologie du Développement de Marseille (IBDM, IFR 15),
Université de la Méditerranée, Marseille, France
Naus, C.C.G. (e-mail: [email protected])
Department of Cellular and Physiological Sciences, Faculty of Medicine,
The University of British Columbia, Vancouver, BC V6R 1W9, Canada
Nlend, R.N.
Department of Cell Physiology and Metabolism, University of Geneva,
Medical School, 1211 Genève 4, Switzerland
Petit, C.
INSERM U587, Unité de Génétique des Déficits Sensoriels, Institut Pasteur,
25, rue du Dr Roux. 75724 Paris Cedex 15, France
Peyrou, M.
Department of Cell Physiology and Metabolism, University of Geneva,
Medical School, 1211 Genève 4, Switzerland
Populaire, C.
Department of Cell Physiology and Metabolism, University of Geneva,
Medical School, 1211 Genève 4, Switzerland
Richard, G. (e-mail: [email protected])
GeneDx Inc., 207 Perry Parkway, Gaithersburg, MD 20877, USA
Severs, N.J. (e-mail: [email protected])
Cardiac Medicine, National Heart and Lung Institute (Imperial College),
Guy Scadding Building, Dovehouse Street, London SW3 6LY, UK
Teunissen, B.E.J.
Department of Medical Physiology, University Medical Center, Utrecht, The
Netherlands
Théveniau-Ruissy, M.
Laboratoire de Génétique et Physiologie du Développement (UMR CNRS
6545), Institut de Biologie du Développement de Marseille (IBDM, IFR 15),
Université de la Méditerranée, Marseille, France
Contributors
XVII
Thomas, N.
National Heart and Lung Institute, Imperial College London, UK
White, T.W. (e-mail: [email protected])
Program in Genetics, Department of Physiology and Biophysics, BST 5–
147, State University of New York, Stony Brook, New York 11794–8661,
USA
Willecke, K. (e-mail: [email protected])
Institut für Genetik, Abt. Molekulargenetik, Römerstr. 164, 53117 Bonn,
Germany
Winterhager, E.
Institute of Anatomy, University of Essen, Essen, Germany
Zulianello, L.
Department of Cell Physiology and Metabolism, University of Geneva,
Medical School, 1211 Genève 4, Switzerland
1
Connexin and Pannexin Genes
in the Mouse and Human Genome
Klaus Willecke, Jürgen Eiberger, Julia von Maltzahn1
1.1
Introduction
Up to the present (December 2004), 20 connexin genes have been identified in the mouse genome. For almost all of them, with the exception
of connexin33, orthologous genes appear to occur in the human genome.
In addition, two connexin genes, i.e. connexin25 and connexin59 appear
to be only present in the human genome which thus contains 21 human
connexin genes. The criteria for the identification of connexin genes in
the genomic data bases and the chromosomal location of these genes have
been described in a recent review article (Söhl and Willecke 2003). This
article also included a comparison of the connexin nomenclature, where
the “Cx” symbol is followed by the theoretical molecular mass (in kDa) of
the corresponding connexin proteins. The alternative nomenclature uses
the letters Gja to Gjd, followed by a consecutive number assigned to each
connexin. The corresponding human connexin gene symbols are GJA to
GJD, followed by the same number as the mouse connexin genes (cf. Söhl
and Willecke 2003).
For the purpose of this volume, in which the expression and function of many connexin genes are discussed, we thought it appropriate to
present an updated list of the mouse and human connexins (see Table 1.1).
With the additions discussed below, this table is very similar to the previously published table (Söhl and Willecke 2003). Thus, we refer the reader
to the previous table regarding all details or questions not mentioned
below.
Five years ago, another class of genes was described which apparently
codes for pannexin proteins in higher vertebrates, including mouse and
man (Panchin et al. 2000). This class of genes shows high sequence homology to innexins that form gap junction channels in invertebrates (for
review, see Phelan 2004). Recently, it has been shown that rat pannexin1
and -2 proteins can form gap junction channels after expression in Xenopus
oocytes. Therefore, at the end of this short review, we have summarized the
1 Institut für Genetik, Abt. Molekulargenetik, Römerstr. 164, 53117 Bonn, Germany, E-mail:
[email protected]
Gap Junctions in Development and Disease
(ed. by E. Winterhager)
c Springer-Verlag Berlin Heidelberg 2005
2
K. Willecke et al.
Table 1.1. Summary of currently known mouse and human connexin genes (orthologues
are listed in line) comparing phenotypes of Cx-deficient mice to known hereditary diseases.
This table represents an updated version of Table 3 published by Söhl and Willecke (2003)
and includes new information on the characterization of several connexin genes discussed
in this chapter
Mouse
connexin
Major
expression
Phenotype(s)
of Cx-deficient
mice
Human
hereditary
disease(s)
Human
connexin
mCx23
n.a.
n.a.
Breast, skin,
cochlea, liver,
placenta
n.a.
n.a.
n.a.
Sensorineural
hearing loss,
palmoplantar
hyperkeratosis,
keratitisichthyosisdeafness
syndrome (KID),
hystrix-like
ichthyosis–
deafness
syndrome
(HID),
Vohwinkel’s
syndrome
n.a.
hCx23
hCx25
hCx26
mCx26
mCx29
mCx30
mCx30.2
mCx30.3
Schwann cells,
oligodendrocytes
Skin, brain,
cochlea
Vascular
smooth muscle
cells, cardiac
conduction
system
Skin
Lethal on ED 11
OTO-cre:
hearing loss
n.a.
Hearing loss
n.a.
n.a.
Nonsyndromic
hearing loss,
hydrotic
ectodermal
dysplasia,
keratitisichthyosisdeafness
syndrome (KID),
Clouston’s
syndrome
n.a.
Erythrokeratodermia variabilis
(EKV)
hCx30.2
(hCx31.3)
hCx30
hCx31.9
hCx30.3
Connexin and Pannexin Genes in the Mouse and Human Genome
3
Table 1.1. (continued)
Mouse
connexin
Major
expression
Phenotype(s)
of Cx-deficient
mice
Human
hereditary
disease(s)
Human
connexin
mCx31
Skin, cochlea,
placenta,
uterus
Placental
dysfunction
Hearing
impairment,
erythrokeratodermia
variabilis
(EKV)
n.a.
hCx31
mCx31.1
Skin
n.a.
mCx32
Liver, Schwann
cells
CMTX
(CharcotMarie-Tooth
neuropathy)
hCx32
mCx33
Testis
Decreased
glycogen
mobilization,
increased liver
carcinogenesis,
CMTX
n.a.
mCx36
(Inter)neurons
n.a.
hCx36
mCx37
Endothelium
Visual
transmission
defects
Female
sterility
hCx37
mCx39
Developing
striated muscle
fibers
Heart,
endothelium
Many cell
types
Association
with
atherosclerosis
n.a.
hCx40.1
n.a.
hCx40
Visceroatrial
heterotaxia
oculodentodigital
dysplasia
syndrome
(ODDD)
syndactyly
type III
n.a.
hCx43a
mCx40
mCx43
mCx45
Heart, smooth
muscle,
neurons
n.a.
Atrial
arrythmias
Lethal on P0
heart
malformations
MHC-cre:
arrythmias
GFAP-cre:
dysregulation
of spreading
depression
Lethal
on ED 10.5
Nestin-cre:
visual
transmission
defects
hCx31.1
hCx45
4
K. Willecke et al.
Table 1.1. (continued)
Mouse
connexin
Major
expression
Phenotype(s)
of Cx-deficient
mice
Human
hereditary
disease(s)
Human
connexin
mCx46
Lens fiber cells
n.a.
hCx46
mCx47
Oligodendrocytes
Zonular
nuclear
cataract
Myelin
deformation
mCx50
Lens fiber cells
mCx57
n.a.
Retinal
horizontal cells
Σ 20
PelizaeusMerzbacherlike disease
(PMLD)
Microphthalmia, Zonular
zonular
pulverulent
pulverulent
cataract
and congenital
cataract
n.a.
n. a.
n.a.
hCx47
hCx50
hCx59
hCx62
Σ 21
a
At the time of writing this review (i.e. December 2004), the human genomic data base
lists an additional human Cx43 gene, located on human chromosome 5 that was previously
described as a pseudogene, based on the absence of an intron and the presence of
a short polyA tail (i.e. ten residues) within the genomic sequence. This pseudogene was
abbreviated to hpsiCx43 by Söhl and Willecke (2003). The hCx43 gene and the hpsiCx43
pseudogene differ in a few nucleotide alterations, but the hpsiCx43 sequence does not
contain any frameshift or nonsense mutation. Thus, both genes hCx43 and hpsiCx43 might
have been subjected to selective pressure during evolution. Thus, the current data bases list
the hpsiCx43 gene as a hypothetically expressed connexin gene. This hypothesis could be
experimentally checked in the future.
Table 1.2. Comparison of mouse and human pannexin proteins and the chromosomal
assignments of their genes
a
Mouse
pannexin
Protein
(aa)
Protein
(kDa)
Chromosome
Human
pannexin
Protein
(aa)
Protein
(kDa)
Chromosome
Panx1
Panx2
Panx3
448a
607a
392a
48.07b
73.27b
44.98b
11a
22a
11a
PANX1
PANX2
PANX3
426b
633b
392b
47.6b
69.5b
44.7b
9b
15b
9b
Baranova et al. (2004); b Bruzzone et al. (2003)