FoxH1 (Fast) functions to specify the anterior primitive streak in the mouse.

The node and the anterior visceral endoderm (AVE) are important organizing centers that pattern the mouse embryo by establishing the anterior-posterior (A-P), dorsal-ventral (D-V), and left-right (L-R) axes. Activin/nodal signaling through the Smad2 pathway has been implicated in AVE formation and in morphogenesis of the primitive streak, the anterior end of which gives rise to the node. The forkhead DNA-binding protein, FoxH1 (or Fast), functions as a Smad DNA-binding partner to regulate transcription in response to activin signaling. Here, we show that deletion of FoxH1 in mice results in failure to pattern the anterior primitive streak (APS) and form node, prechordal mesoderm, notochord, and definitive endoderm. In contrast, formation of the AVE can occur in the absence of FoxH1. The FoxH1 mutant phenotype is remarkably similar to that of mice deficient in the forkhead protein Foxa2 (HNF3beta), and we show that Foxa2 expression is dependent on FoxH1 function. These results show that FoxH1 functions in an activin/nodal-Smad signaling pathway that acts upstream of Foxa2 and is required specifically for patterning the APS and node in the mouse.

[1]  A. Schier.  Nodal signaling in vertebrate development. , 2003, Annual review of cell and developmental biology.

[2]  Y. Saijoh,et al.  The transcription factor FoxH1 (FAST) mediates Nodal signaling during anterior-posterior patterning and node formation in the mouse. , 2001, Genes & development.

[3]  L. Goldstein,et al.  Functional Analysis of Mouse C-Terminal Kinesin Motor KifC2 , 2001, Molecular and Cellular Biology.

[4]  A. Celeste,et al.  Nodal Signaling Uses Activin and Transforming Growth Factor-β Receptor-regulated Smads* , 2001, The Journal of Biological Chemistry.

[5]  P. Tam,et al.  The node of the mouse embryo , 2000, Current Biology.

[6]  M. Gates,et al.  fast1 is required for the development of dorsal axial structures in zebrafish , 2000, Current Biology.

[7]  W. Driever,et al.  The zebrafish forkhead transcription factor FoxH1/Fast1 is a modulator of Nodal signaling required for organizer formation , 2000, Current Biology.

[8]  P. Hoodless,et al.  Formation of the definitive endoderm in mouse is a Smad2-dependent process. , 2000, Development.

[9]  R. Beddington,et al.  Development of chick axial mesoderm: specification of prechordal mesoderm by anterior endoderm-derived TGFbeta family signalling. , 2000, Development.

[10]  Y. Saijoh,et al.  Activin/nodal responsiveness and asymmetric expression of a Xenopus nodal-related gene converge on a FAST-regulated module in intron 1. , 2000, Development.

[11]  D. Kioussis,et al.  The homeobox gene Hex is required in definitive endodermal tissues for normal forebrain, liver and thyroid formation. , 2000, Development.

[12]  D. Melton,et al.  Early mouse endoderm is patterned by soluble factors from adjacent germ layers. , 2000, Development.

[13]  J. Wrana,et al.  Smads as transcriptional co-modulators. , 2000, Current opinion in cell biology.

[14]  S. Germain,et al.  Homeodomain and winged-helix transcription factors recruit activated Smads to distinct promoter elements via a common Smad interaction motif. , 2000, Genes & development.

[15]  Ryan M. Anderson,et al.  The organizer factors Chordin and Noggin are required for mouse forebrain development , 2000, Nature.

[16]  Minoru Watanabe,et al.  FAST-1 is a key maternal effector of mesoderm inducers in the early Xenopus embryo. , 1999, Development.

[17]  R. Nagarajan,et al.  Smad3 Inhibits Transforming Growth Factor-β and Activin Signaling by Competing with Smad4 for FAST-2 Binding* , 1999, The Journal of Biological Chemistry.

[18]  R. Kucherlapati,et al.  Postgastrulation Smad2-deficient embryos show defects in embryo turning and anterior morphogenesis. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[19]  P. Hoodless,et al.  Dominant-negative Smad2 mutants inhibit activin/Vg1 signaling and disrupt axis formation in Xenopus. , 1999, Developmental biology.

[20]  R. Beddington,et al.  Axis Development and Early Asymmetry in Mammals , 1999, Cell.

[21]  E. Lai,et al.  FAST-2 Is a Mammalian Winged-Helix Protein Which Mediates Transforming Growth Factor β Signals , 1999, Molecular and Cellular Biology.

[22]  B. Hogan,et al.  A mouse homologue of FAST-1 transduces TGFβ superfamily signals and is expressed during early embryogenesis , 1998, Mechanisms of Development.

[23]  J. Rossant,et al.  The transcription factor HNF3beta is required in visceral endoderm for normal primitive streak morphogenesis. , 1998, Development.

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

[25]  C. Deng,et al.  Failure of egg cylinder elongation and mesoderm induction in mouse embryos lacking the tumor suppressor smad2. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[26]  P. Lemaire,et al.  A novel Xenopus mix-like gene milk involved in the control of the endomesodermal fates. , 1998, Development.

[27]  D. Melton,et al.  Mixer, a homeobox gene required for endoderm development. , 1998, Science.

[28]  P. Hoodless,et al.  Smad2 and Smad3 positively and negatively regulate TGF beta-dependent transcription through the forkhead DNA-binding protein FAST2. , 1998, Molecular cell.

[29]  K. Kinzler,et al.  Characterization of human FAST-1, a TGFβ and activin signal transducer , 1998 .

[30]  E. Li,et al.  Smad2 role in mesoderm formation, left–right patterning and craniofacial development , 1998, Nature.

[31]  P. Hoodless,et al.  Smad2 Signaling in Extraembryonic Tissues Determines Anterior-Posterior Polarity of the Early Mouse Embryo , 1998, Cell.

[32]  P. Donahoe,et al.  The type I activin receptor ActRIB is required for egg cylinder organization and gastrulation in the mouse. , 1998, Genes & development.

[33]  M. Howell,et al.  XSmad2 directly activates the activin‐inducible, dorsal mesoderm gene XFKH1 in Xenopus embryos , 1997, The EMBO journal.

[34]  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.

[35]  R. Behringer,et al.  Goosecoid and HNF-3beta genetically interact to regulate neural tube patterning during mouse embryogenesis. , 1997, Development.

[36]  J. Collignon,et al.  nodal expression in the primitive endoderm is required for specification of the anterior axis during mouse gastrulation. , 1997, Development.

[37]  Xin Chen,et al.  A transcriptional partner for MAD proteins in TGF-β signalling , 1996, Nature.

[38]  R. Behringer,et al.  Requirement for LIml in head-organizer function , 1995, Nature.

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

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

[41]  F. Conlon,et al.  A primary requirement for nodal in the formation and maintenance of the primitive streak in the mouse. , 1994, Development.

[42]  J. Rossant,et al.  The formation and maintenance of the definitive endoderm lineage in the mouse: involvement of HNF3/forkhead proteins. , 1993, Development.

[43]  J. Darnell,et al.  Sequential expression of HNF-3β and HNF-3α by embryonic organizing centers: the dorsal lip/node, notochord and floor plate , 1993, Mechanisms of Development.

[44]  K. Kaestner,et al.  Postimplantation expression patterns indicate a role for the mouse forkhead/HNF-3 alpha, beta and gamma genes in determination of the definitive endoderm, chordamesoderm and neuroectoderm. , 1993, Development.

[45]  Linda Lowe,et al.  Nodal is a novel TGF-β-like gene expressed in the mouse node during gastrulation , 1993, Nature.

[46]  R. Pedersen,et al.  Clonal analysis of epiblast fate during germ layer formation in the mouse embryo. , 1991, Development.

[47]  R. Beddington,et al.  An assessment of the developmental potential of embryonic stem cells in the midgestation mouse embryo. , 1989, Development.

[48]  Y. Saijoh,et al.  Two-step regulation of left-right asymmetric expression of Pitx2: initiation by nodal signaling and maintenance by Nkx2. , 2001, Molecular cell.

[49]  Y. Saijoh,et al.  Left-right asymmetric expression of lefty2 and nodal is induced by a signaling pathway that includes the transcription factor FAST2. , 2000, Molecular cell.

[50]  J. Wrana,et al.  Mechanisms and biology of signaling by serine/threonine kinase receptors for the TGFb superfamily , 2000 .

[51]  D. Melton,et al.  Vertebrate endoderm development. , 1999, Annual review of cell and developmental biology.

[52]  R. Beddington,et al.  Hex: a homeobox gene revealing peri-implantation asymmetry in the mouse embryo and an early transient marker of endothelial cell precursors. , 1998, Development.

[53]  J. Gerhart,et al.  Formation and function of Spemann's organizer. , 1997, Annual review of cell and developmental biology.

[54]  S. Mackem,et al.  Rpx: a novel anterior-restricted homeobox gene progressively activated in the prechordal plate, anterior neural plate and Rathke's pouch of the mouse embryo. , 1996, Development.

[55]  N. Daigle,et al.  A targeted mouse Otx2 mutation leads to severe defects in gastrulation and formation of axial mesoderm and to deletion of rostral brain. , 1996, Development.

[56]  K. Kaestner,et al.  Postimplantation expression patterns indicate a role for the mouse forkhead /HNF-3 , and genes in determination of the definitive endoderm, chordamesoderm and neuroectoderm , 1996 .