FKBP8 is a negative regulator of mouse sonic hedgehog signaling in neural tissues

Sonic hedgehog (SHH) is a secreted morphogen that regulates the patterning and growth of many tissues in the developing mouse embryo, including the central nervous system (CNS). We show that a member of the FK506-binding protein family, FKBP8, is an essential antagonist of SHH signaling in CNS development. Loss of FKBP8 causes ectopic and ligand-independent activation of the Shh pathway, leading to expansion of ventral cell fates in the posterior neural tube and suppression of eye development. Although it is expressed broadly, FKBP8 is required to antagonize SHH signaling primarily in neural tissues, suggesting that hedgehog signal transduction is subject to cell-type specific modulation during mammalian development.

[1]  Lee Niswander,et al.  Hedgehog signalling in the mouse requires intraflagellar transport proteins , 2003, Nature.

[2]  Jason C. Young,et al.  More than folding: localized functions of cytosolic chaperones. , 2003, Trends in biochemical sciences.

[3]  M. Scott,et al.  Differential requirement for Gli2 and Gli3 in ventral neural cell fate specification. , 2003, Developmental biology.

[4]  W. Harris,et al.  A novel function for Hedgehog signalling in retinal pigment epithelium differentiation , 2003, Development.

[5]  Jens Böse,et al.  Dorsal-ventral patterning of the spinal cord requires Gli3 transcriptional repressor activity. , 2002, Genes & development.

[6]  A. McMahon,et al.  A direct requirement for Hedgehog signaling for normal specification of all ventral progenitor domains in the presumptive mammalian spinal cord. , 2002, Genes & development.

[7]  A. McMahon,et al.  A sonic hedgehog-dependent signaling relay regulates growth of diencephalic and mesencephalic primordia in the early mouse embryo. , 2002, Development.

[8]  Norbert Perrimon,et al.  Hedgehog signal transduction: recent findings. , 2002, Current opinion in genetics & development.

[9]  Rolf Zeller,et al.  Progression of Vertebrate Limb Development Through SHH-Mediated Counteraction of GLI3 , 2002, Science.

[10]  Christian Knaak,et al.  Megalin Functions as an Endocytic Sonic Hedgehog Receptor* , 2002, The Journal of Biological Chemistry.

[11]  G. McKnight,et al.  Protein Kinase A Deficiency Causes Axially Localized Neural Tube Defects in Mice* , 2002, The Journal of Biological Chemistry.

[12]  Andrew P McMahon,et al.  A mitogen gradient of dorsal midline Wnts organizes growth in the CNS. , 2002, Development.

[13]  Benoit Robert,et al.  Characterization of a Smad motif similar to Drosophila mad in the mouse Msx 1 promoter. , 2002, Biochemical and biophysical research communications.

[14]  H. Kondoh,et al.  Wnt signaling plays an essential role in neuronal specification of the dorsal spinal cord. , 2002, Genes & development.

[15]  Paola Bovolenta,et al.  Sonic hedgehog in CNS development: one signal, multiple outputs , 2002, Trends in Neurosciences.

[16]  P. Ingham,et al.  Hedgehog signaling in animal development: paradigms and principles. , 2001, Genes & development.

[17]  I. Kirsch,et al.  Genetic evidence that Sil is required for the sonic hedgehog response pathway , 2001, Genesis.

[18]  L. Buttitta,et al.  Evidence that the WNT-inducible growth arrest-specific gene 1 encodes an antagonist of sonic hedgehog signaling in the somite , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[19]  C. Tabin,et al.  Comparative biological responses to human Sonic, Indian, and Desert hedgehog , 2001, Mechanisms of Development.

[20]  K. Anderson,et al.  Rab23 is an essential negative regulator of the mouse Sonic hedgehog signalling pathway , 2001, Nature.

[21]  Andrew P. McMahon,et al.  Smoothened Mutants Reveal Redundant Roles for Shh and Ihh Signaling Including Regulation of L/R Asymmetry by the Mouse Node , 2001, Cell.

[22]  D. Hong,et al.  Retinitis Pigmentosa GTPase Regulator (RPGR)-interacting Protein Is Stably Associated with the Photoreceptor Ciliary Axoneme and Anchors RPGR to the Connecting Cilium* , 2001, The Journal of Biological Chemistry.

[23]  N. Méthot,et al.  An absolute requirement for Cubitus interruptus in Hedgehog signaling. , 2001, Development.

[24]  T. Jessell,et al.  Control of Interneuron Fate in the Developing Spinal Cord by the Progenitor Homeodomain Protein Dbx1 , 2001, Neuron.

[25]  J. Briscoe,et al.  Specification of neuronal fates in the ventral neural tube , 2001, Current Opinion in Neurobiology.

[26]  K. Anderson,et al.  Dorsal and lateral fates in the mouse neural tube require the cell-autonomous activity of the open brain gene. , 2000, Developmental biology.

[27]  T. Jessell,et al.  Regulation of the neural patterning activity of sonic hedgehog by secreted BMP inhibitors expressed by notochord and somites. , 2000, Development.

[28]  C. Chiang,et al.  Specification of ventral neuron types is mediated by an antagonistic interaction between Shh and Gli3 , 2000, Nature Neuroscience.

[29]  T. Jessell.  Neuronal specification in the spinal cord: inductive signals and transcriptional codes , 2000, Nature Reviews Genetics.

[30]  Philip A Beachy,et al.  Hedgehog-Regulated Processing of Gli3 Produces an Anterior/Posterior Repressor Gradient in the Developing Vertebrate Limb , 2000, Cell.

[31]  L. Goldstein,et al.  Kinesin-II Is Required for Axonal Transport of Choline Acetyltransferase in Drosophila , 1999, The Journal of cell biology.

[32]  M. Scott,et al.  Mouse patched1 controls body size determination and limb patterning. , 1999, Development.

[33]  D. Kalderon,et al.  Proteolysis of cubitus interruptus in Drosophila requires phosphorylation by protein kinase A. , 1999, Development.

[34]  T. Pietri,et al.  Differential requirements of the fused kinase for hedgehog signalling in the Drosophila embryo. , 1999, Development.

[35]  T. Jessell,et al.  A Sonic Hedgehog–Independent, Retinoid-Activated Pathway of Neurogenesis in the Ventral Spinal Cord , 1999, Cell.

[36]  J. Rubenstein,et al.  Homeobox gene Nkx2.2 and specification of neuronal identity by graded Sonic hedgehog signalling , 1999, Nature.

[37]  Pao-Tien Chuang,et al.  Vertebrate Hedgehog signalling modulated by induction of a Hedgehog-binding protein , 1999, Nature.

[38]  J. Celis,et al.  muFKBP38: A novel murine immunophilin homolog differentially expressed in Schwannoma cells and central nervous system neurons in vivo , 1999, Electrophoresis.

[39]  D. Kalderon,et al.  Hedgehog stimulates maturation of Cubitus interruptus into a labile transcriptional activator , 1998, Nature.

[40]  T. Jessell,et al.  Neuronal patterning by BMPs: a requirement for GDF7 in the generation of a discrete class of commissural interneurons in the mouse spinal cord. , 1998, Genes & development.

[41]  S. Snyder,et al.  Immunophilins in the Nervous System , 1998, Neuron.

[42]  A. Joyner,et al.  Gli2 is required for induction of floor plate and adjacent cells, but not most ventral neurons in the mouse central nervous system. , 1998, Development.

[43]  T. Bouwmeester,et al.  Cerberus-like is a secreted factor with neuralizing activity expressed in the anterior primitive endoderm of the mouse gastrula , 1997, Mechanisms of Development.

[44]  M. Scott,et al.  Altered neural cell fates and medulloblastoma in mouse patched mutants. , 1997, Science.

[45]  R. Kobayashi,et al.  Hedgehog Elicits Signal Transduction by Means of a Large Complex Containing the Kinesin-Related Protein Costal2 , 1997, Cell.

[46]  B. Hogan,et al.  Bone morphogenetic proteins (BMPs) as regulators of dorsal forebrain development. , 1997, Development.

[47]  M. Nakafuku,et al.  A binding site for Gli proteins is essential for HNF-3beta floor plate enhancer activity in transgenics and can respond to Shh in vitro. , 1997, Development.

[48]  C. Tabin,et al.  Biochemical evidence that Patched is the Hedgehog receptor , 1996, Nature.

[49]  G. Struhl,et al.  Dual Roles for Patched in Sequestering and Transducing Hedgehog , 1996, Cell.

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

[51]  S. Snyder,et al.  Calcineurin associated with the inositol 1,4,5-trisphosphate receptor-FKBP12 complex modulates Ca2+ flux , 1995, Cell.

[52]  Stephen W. Wilson,et al.  Midline signalling is required for Pax gene regulation and patterning of the eyes. , 1995, Development.

[53]  T. Jessell,et al.  Dorsal differentiation of neural plate cells induced by BMP-mediated signals from epidermal ectoderm , 1995, Cell.

[54]  R. Moon,et al.  Patterning activities of vertebrate hedgehog proteins in the developing eye and brain , 1995, Current Biology.

[55]  T. Jessell,et al.  Floor plate and motor neuron induction by different concentrations of the amino-terminal cleavage product of sonic hedgehog autoproteolysis , 1995, Cell.

[56]  K. Schughart,et al.  Open brain, a new mouse mutant with severe neural tube defects, shows altered gene expression patterns in the developing spinal cord. , 1994, Development.

[57]  C. Zuker,et al.  Genetic dissection of mechanosensory transduction: Mechanoreception-defective mutations of drosophila , 1994, Neuron.

[58]  Andrew P. McMahon,et al.  Sonic hedgehog, a member of a family of putative signaling molecules, is implicated in the regulation of CNS polarity , 1993, Cell.

[59]  N. Schaeren-Wiemers,et al.  A single protocol to detect transcripts of various types and expression levels in neural tissue and cultured cells: in situ hybridization using digoxigenin-labelled cRNA probes , 1993, Histochemistry.

[60]  B. Kirchhof,et al.  Repair of outer blood-retinal barrier after severe ocular blunt trauma in rabbits , 1993, Graefe's Archive for Clinical and Experimental Ophthalmology.

[61]  B. Hogan,et al.  Differential expression of multiple fork head related genes during gastrulation and axial pattern formation in the mouse embryo. , 1993, Development.

[62]  G. Crabtree,et al.  Identification of calcineurin as a key signalling enzyme in T-lymphocyte activation , 1992, Nature.

[63]  H. Erdjument-Bromage,et al.  FK506 binding protein associated with the calcium release channel (ryanodine receptor). , 1992, The Journal of biological chemistry.

[64]  G. Saunders,et al.  Mouse Small eye results from mutations in a paired-like homeobox-containing gene , 1991, Nature.

[65]  P. Gruss,et al.  Pax-6, a murine paired box gene, is expressed in the developing CNS. , 1991, Development.

[66]  K. Nakayama,et al.  Inherent calcineurin inhibitor FKBP38 targets Bcl-2 to mitochondria and inhibits apoptosis , 2003, Nature Cell Biology.

[67]  A. Joyner,et al.  Gli 2 is required for induction of floor plate and adjacent cells , but not most ventral neurons in the mouse central nervous system , 1998 .

[68]  T. Jessell,et al.  Graded sonic hedgehog signaling and the specification of cell fate in the ventral neural tube. , 1997, Cold Spring Harbor symposia on quantitative biology.

[69]  博樹 東海林.  Regionalized expression of the Dbx family homeobox genes in the embryonic CNS of the mouse , 1996 .