The Opitz syndrome gene MID1 is essential for establishing asymmetric gene expression in Hensen's node.

Patterning the avian left-right (L/R) body axis involves the establishment of asymmetric molecular signals on the left and right sides of Hensen's node. We have examined the role of the chick Midline 1 gene, cMid1, in generating asymmetric gene expression in the node. cMid1 is initially expressed bilaterally, but its expression is then confined to the right side of the node. We show that this restriction of cMid1 expression is a result of repression by Shh on the left side of the node. Misexpression of cMid1 on the left side of the node results in bilateral Bmp4 expression and a loss of Shh expression. Correspondingly, downstream left pathway genes are repressed while right pathway genes are ectopically activated. Conversely, knocking down endogenous right-sided cMid1 results in a loss of Bmp4 expression and bilateral Shh expression. This results in an absence of right pathway genes and the ectopic activation of the left pathway on the right. Here, we present a revised model for the establishment of asymmetric gene expression in Hensen's node based on the epistatic interactions observed between Shh, cMid1, and Bmp4.

[1]  K. Grzeschik,et al.  GLI3 zinc-finger gene interrupted by translocations in Greig syndrome families , 1991, Nature.

[2]  M. Mercola,et al.  Asymmetries in H+/K+-ATPase and Cell Membrane Potentials Comprise a Very Early Step in Left-Right Patterning , 2002, Cell.

[3]  A. Ballabio,et al.  MID2, a homologue of the Opitz syndrome gene MID1: similarities in subcellular localization and differences in expression during development. , 1999, Human molecular genetics.

[4]  T. Cox,et al.  Isolation and characterisation of the chick orthologue of the Opitz syndrome gene, Mid1, supports a conserved role in vertebrate development. , 2002, The International journal of developmental biology.

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

[6]  E. Sontag.  Protein phosphatase 2A: the Trojan Horse of cellular signaling. , 2001, Cellular signalling.

[7]  H. Ropers,et al.  MID1, mutated in Opitz syndrome, encodes an ubiquitin ligase that targets phosphatase 2A for degradation , 2001, Nature Genetics.

[8]  R. Myers,et al.  Human Homolog of patched, a Candidate Gene for the Basal Cell Nevus Syndrome , 1996, Science.

[9]  C. Tabin,et al.  Left–right development: Conserved function for embryonic nodal cilia , 2002, Nature.

[10]  Michael Dean,et al.  Mutations of the Human Homolog of Drosophila patched in the Nevoid Basal Cell Carcinoma Syndrome , 1996, Cell.

[11]  Clifford J. Tabin,et al.  The Transfer of Left-Right Positional Information during Chick Embryogenesis , 1998, Cell.

[12]  A. Ballabio,et al.  Opitz G/BBB syndrome in Xp22: mutations in the MID1 gene cluster in the carboxy-terminal domain. , 1998, American journal of human genetics.

[13]  A. Monsoro-Burq,et al.  BMP4 plays a key role in left-right patterning in chick embryos by maintaining Sonic Hedgehog asymmetry. , 2001, Molecular cell.

[14]  N. Nakanishi,et al.  The role of an endogenous PKA inhibitor, PKIalpha, in organizing left-right axis formation. , 2001, Development.

[15]  George J. Feldman,et al.  Opitz G/BBB syndrome, a defect of midline development, is due to mutations in a new RING finger gene on Xp22 , 1997, Nature Genetics.

[16]  C. Helms,et al.  Identification of Sonic hedgehog as a candidate gene responsible for holoprosencephaly , 1996, Nature Genetics.

[17]  S. Scherer,et al.  Mutations in the human Sonic Hedgehog gene cause holoprosencephaly , 1996, Nature Genetics.

[18]  E. Haan,et al.  New mutations in MID1 provide support for loss of function as the cause of X-linked Opitz syndrome. , 2000, Human molecular genetics.

[19]  S. Chapman,et al.  Improved method for chick whole‐embryo culture using a filter paper carrier , 2001, Developmental dynamics : an official publication of the American Association of Anatomists.

[20]  M. Bronner‐Fraser,et al.  N-Cadherin, a cell adhesion molecule involved in establishment of embryonic left-right asymmetry. , 2000, Science.

[21]  J. Cooke,et al.  Left/right patterning signals and the independent regulation of different aspects of situs in the chick embryo. , 1997, Developmental biology.

[22]  J. Cooke,et al.  Control of Vertebrate Left-Right Asymmetry by a Snail-Related Zinc Finger Gene , 1997, Science.

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

[24]  M. Muenke,et al.  Midline and laterality defects: Left and right meet in the middle † , 2001, BioEssays : news and reviews in molecular, cellular and developmental biology.

[25]  J. I. Izpisúa Belmonte,et al.  Wnt signaling and PKA control Nodal expression and left-right determination in the chick embryo. , 2001, Development.

[26]  C. V. Wright.  Mechanisms of left-right asymmetry: what's right and what's left? , 2001, Developmental cell.

[27]  M. Mercola,et al.  Gap junction-mediated transfer of left-right patterning signals in the early chick blastoderm is upstream of Shh asymmetry in the node , 1999 .

[28]  C. Tabin,et al.  A molecular pathway determining left-right asymmetry in chick embryogenesis , 1995, Cell.

[29]  G. Meroni,et al.  Phosphorylation and microtubule association of the Opitz syndrome protein mid-1 is regulated by protein phosphatase 2A via binding to the regulatory subunit α4 , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[30]  M. Kessel,et al.  FGF8 functions in the specification of the right body side of the chick , 1999, Current Biology.

[31]  Johan Ericson,et al.  Two Critical Periods of Sonic Hedgehog Signaling Required for the Specification of Motor Neuron Identity , 1996, Cell.

[32]  J. Lewis,et al.  A chick homologue of Serrate and its relationship with Notch and Delta homologues during central neurogenesis. , 1996, Developmental biology.