A complex syndrome of left-right axis, central nervous system and axial skeleton defects in Zic3 mutant mice.

X-linked heterotaxy (HTX1) is a rare developmental disorder characterized by disturbances in embryonic laterality and other midline developmental field defects. HTX1 results from mutations in ZIC3, a member of the GLI transcription factor superfamily. A targeted deletion of the murine Zic3 locus has been created to investigate its function and interactions with other molecular components of the left-right axis pathway. Embryonic lethality is seen in approximately 50% of null mice with an additional 30% lethality in the perinatal period. Null embryos have defects in turning, cardiac development and neural tube closure. Malformations in live born null mice include complex congenital heart defects, pulmonary reversal or isomerism, CNS defects and vertebral/rib anomalies. Investigation of nodal expression in Zic3-deficient mice indicates that, although nodal is initially expressed symmetrically in the node, there is failure to maintain expression and to shift to asymmetric expression. Subsequent nodal and Pitx2 expression in the lateral plate mesoderm in these mice is randomized, indicating that Zic3 acts upstream of these genes in the determination of left-right asymmetry. The phenotype of these mice correctly models the defects found in human HTX1 and indicates an important role for Zic3 in both left-right and axial patterning.

[1]  K. Mikoshiba,et al.  Physical and Functional Interactions between Zic and Gli Proteins* , 2001, The Journal of Biological Chemistry.

[2]  R. Kosaki,et al.  Mutation analysis of left-right axis determining genes in NOD and ICR, strains susceptible to maternal diabetes. , 2001, Teratology.

[3]  K. Mikoshiba,et al.  Molecular Properties of Zic Proteins as Transcriptional Regulators and Their Relationship to GLI Proteins* , 2001, The Journal of Biological Chemistry.

[4]  K. Mikoshiba,et al.  A novel member of the Xenopus Zic family, Zic5, mediates neural crest development , 2000, Mechanisms of Development.

[5]  K. Mikoshiba,et al.  Zic3 is involved in the left-right specification of the Xenopus embryo. , 2000, Development.

[6]  Alexander F. Schier,et al.  Loss-of-function mutations in the EGF-CFC gene CFC1 are associated with human left-right laterality defects , 2000, Nature Genetics.

[7]  A. Mégarbané,et al.  X-linked transposition of the great arteries and incomplete penetrance among males with a nonsense mutation in ZIC3 , 2000, European Journal of Human Genetics.

[8]  G. Herman,et al.  The X-linked mouse mutation Bent tail is associated with a deletion of the Zic3 locus. , 2000, Human molecular genetics.

[9]  B. Franke,et al.  A deletion encompassing Zic3 in bent tail, a mouse model for X-linked neural tube defects. , 2000, Human molecular genetics.

[10]  B. Casey,et al.  Left-right axis malformations in man and mouse. , 2000, Current opinion in genetics & development.

[11]  A. Schier,et al.  Conserved and divergent mechanisms in left-right axis formation. , 2000, Genes & development.

[12]  C. Tabin,et al.  Mechanisms of Left–Right Determination in Vertebrates , 2000, Cell.

[13]  C. Rankin,et al.  Regulation of left-right patterning in mice by growth/differentiation factor-1 , 2000, Nature Genetics.

[14]  K. Mikoshiba,et al.  Zic2 regulates the kinetics of neurulation. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[15]  S. Miyagawa-Tomita,et al.  Mouse Pitx2 deficiency leads to anomalies of the ventral body wall, heart, extra- and periocular mesoderm and right pulmonary isomerism. , 1999, Development.

[16]  K. Mikoshiba,et al.  Zic1 regulates the patterning of vertebral arches in cooperation with Gli3 , 1999, Mechanisms of Development.

[17]  D. Supp,et al.  Targeted deletion of the ATP binding domain of left-right dynein confirms its role in specifying development of left-right asymmetries. , 1999, Development.

[18]  W. Talbot,et al.  Conserved requirement for EGF-CFC genes in vertebrate left-right axis formation. , 1999, Genes & development.

[19]  Concepción Rodríguez-Esteban,et al.  Multiple left-right asymmetry defects in Shh(-/-) mutant mice unveil a convergence of the shh and retinoic acid pathways in the control of Lefty-1. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[20]  M. Rosenfeld,et al.  Pitx2 regulates lung asymmetry, cardiac positioning and pituitary and tooth morphogenesis , 1999, Nature.

[21]  Randy L. Johnson,et al.  Function of Rieger syndrome gene in left–right asymmetry and craniofacial development , 1999, Nature.

[22]  W. Talbot,et al.  Mouse Lefty2 and zebrafish antivin are feedback inhibitors of nodal signaling during vertebrate gastrulation. , 1999, Molecular cell.

[23]  G. Martin,et al.  Differences in left-right axis pathways in mouse and chick: functions of FGF8 and SHH. , 1999, Science.

[24]  I. Kirsch,et al.  The SIL gene is required for mouse embryonic axial development and left–right specification , 1999, Nature.

[25]  N. Hirokawa,et al.  Left-Right Asymmetry and Kinesin Superfamily Protein KIF3A: New Insights in Determination of Laterality and Mesoderm Induction by kif3A− /− Mice Analysis , 1999, The Journal of cell biology.

[26]  L. Goldstein,et al.  Situs inversus and embryonic ciliary morphogenesis defects in mouse mutants lacking the KIF3A subunit of kinesin-II. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[27]  C. Viebahn,et al.  The homeobox gene Pitx2: mediator of asymmetric left-right signaling in vertebrate heart and gut looping. , 1999, Development.

[28]  N. Hirokawa,et al.  Randomization of Left–Right Asymmetry due to Loss of Nodal Cilia Generating Leftward Flow of Extraembryonic Fluid in Mice Lacking KIF3B Motor Protein , 1998, Cell.

[29]  C. Cepko,et al.  Granule Cell Raphes and Parasagittal Domains of Purkinje Cells: Complementary Patterns in the Developing Chick Cerebellum , 1998, The Journal of Neuroscience.

[30]  D. Warburton,et al.  Holoprosencephaly due to mutations in ZIC2, a homologue of Drosophila odd-paired , 1998, Nature Genetics.

[31]  J. Chen,et al.  Mutation of the mouse hepatocyte nuclear factor/forkhead homologue 4 gene results in an absence of cilia and random left-right asymmetry. , 1998, The Journal of clinical investigation.

[32]  Paul A. Overbeek,et al.  Cloning of inv, a gene that controls left/right asymmetry and kidney development , 1998, Nature.

[33]  H. Hamada,et al.  Pitx2, a Bicoid-Type Homeobox Gene, Is Involved in a Lefty-Signaling Pathway in Determination of Left-Right Asymmetry , 1998, Cell.

[34]  Y. Saijoh,et al.  lefty-1 Is Required for Left-Right Determination as a Regulator of lefty-2 and nodal , 1998, Cell.

[35]  C. Tabin,et al.  The Transcription Factor Pitx2 Mediates Situs-Specific Morphogenesis in Response to Left-Right Asymmetric Signals , 1998, Cell.

[36]  R. Harvey,et al.  Links in the Left/Right Axial Pathway , 1998, Cell.

[37]  J. Rodríguez-Rey,et al.  Pitx2 Participates in the Late Phase of the Pathway Controlling Left-Right Asymmetry , 1998, Cell.

[38]  J. C. Belmonte,et al.  Pitx2 determines left–right asymmetry of internal organs in vertebrates , 1998, Nature.

[39]  R. Brewster,et al.  Gli/Zic factors pattern the neural plate by defining domains of cell differentiation , 1998, Nature.

[40]  K. Mikoshiba,et al.  Mouse Zic1 Is Involved in Cerebellar Development , 1998, The Journal of Neuroscience.

[41]  D. Schlessinger,et al.  X-linked situs abnormalities result from mutations in ZIC3 , 1997, Nature Genetics.

[42]  D. Supp,et al.  Mutation of an axonemal dynein affects left–right asymmetry in inversus viscerum mice , 1997, Nature.

[43]  K. Mikoshiba,et al.  Xenopus Zic3, a primary regulator both in neural and neural crest development. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[44]  S. P. Oh,et al.  The signaling pathway mediated by the type IIB activin receptor controls axial patterning and lateral asymmetry in the mouse. , 1997, Genes & development.

[45]  K. Mikoshiba,et al.  The expression of the mouse Zic1, Zic2, and Zic3 gene suggests an essential role for Zic genes in body pattern formation. , 1997, Developmental biology.

[46]  P. Beachy,et al.  Cyclopia and defective axial patterning in mice lacking Sonic hedgehog gene function , 1996, Nature.

[47]  V. Chapman,et al.  Identification and characterization of Zic4, a new member of the mouse Zic gene family. , 1996, Gene.

[48]  D. Supp,et al.  Conserved left–right asymmetry of nodal expression and alterations in murine situs inversus , 1996, Nature.

[49]  Y. Saijoh,et al.  Left–right asymmetric expression of the TGFβ-family member lefty in mouse embryos , 1996, Nature.

[50]  J. Collignon,et al.  Relationship between asymmetric nodal expression and the direction of embryonic turning , 1996, Nature.

[51]  R. Behringer,et al.  Müllerian-inhibiting substance function during mammalian sexual development , 1994, Cell.

[52]  K. Mikoshiba,et al.  A Novel Zinc Finger Protein, Zic, Is Involved in Neurogenesis, Especially in the Cell Lineage of Cerebellar Granule Cells , 1994, Journal of neurochemistry.

[53]  Thomas M. Jessell,et al.  The winged-helix transcription factor HNF-3β is required for notochord development in the mouse embryo , 1994, Cell.

[54]  J. Rossant,et al.  HNF-3β is essential for node and notochord formation in mouse development , 1994, Cell.

[55]  A. Ballabio,et al.  Mapping a gene for familial situs abnormalities to human chromosome Xq24-q27.1 , 1993, Nature Genetics.

[56]  N. Copeland,et al.  Reversal of left-right asymmetry: a situs inversus mutation. , 1993, Science.

[57]  E. Garber.  "Bent-Tail," A Dominant, Sex-Linked Mutation in the Mouse. , 1952, Proceedings of the National Academy of Sciences of the United States of America.

[58]  C. Lo,et al.  No turning, a mouse mutation causing left-right and axial patterning defects. , 1998, Developmental biology.

[59]  D. Wilkinson.  In situ hybridization: a practical approach , 1998 .

[60]  K. Hummel,et al.  VISCERAL INVERSION AND ASSOCIATED ANOMALIES IN THE MOUSE , 1959 .