Signaling through BMP receptors promotes respiratory identity in the foregut via repression of Sox2

The mammalian foregut gives rise to the dorsally located esophagus and stomach and the ventrally located trachea and lung. Proper patterning and morphogenesis of the common foregut tube and its derived organs is essential for viability of the organism at birth. Here, we show that conditional inactivation of BMP type I receptor genes Bmpr1a and Bmpr1b (Bmpr1a;b) in the ventral endoderm leads to tracheal agenesis and ectopic primary bronchi. Molecular analyses of these mutants reveal a reduction of ventral endoderm marker NKX2-1 and an expansion of dorsal markers SOX2 and P63 into the prospective trachea and primary bronchi. Subsequent genetic experiments show that activation of canonical WNT signaling, previously shown to induce ectopic respiratory fate in otherwise wild-type mice, is incapable of promoting respiratory fate in the absence of Bmpr1a;b. Furthermore, we find that inactivation of Sox2 in Bmpr1a;b mutants does not suppress ectopic lung budding but does rescue trachea formation and NKX2-1 expression. Together, our data suggest that signaling through BMPR1A;B performs at least two roles in early respiratory development: first, it promotes tracheal formation through repression of Sox2; and second, it restricts the site of lung bud initiation.

[1]  Elizabeth M. Mandel,et al.  The BMP pathway acts to directly regulate Tbx20 in the developing heart , 2010, Development.

[2]  B. Hogan,et al.  Preparing for the first breath: genetic and cellular mechanisms in lung development. , 2010, Developmental cell.

[3]  C. Deng,et al.  The type I BMP receptors, Bmpr1a and Acvr1, activate multiple signaling pathways to regulate lens formation. , 2009, Developmental biology.

[4]  Jessica Mariani,et al.  Hippocampal development and neural stem cell maintenance require Sox2-dependent regulation of Shh , 2009, Nature Neuroscience.

[5]  Eric T. Domyan,et al.  β-Catenin promotes respiratory progenitor identity in mouse foregut , 2009, Proceedings of the National Academy of Sciences.

[6]  M. Lu,et al.  Wnt2/2b and beta-catenin signaling are necessary and sufficient to specify lung progenitors in the foregut. , 2009, Developmental cell.

[7]  R. Lovell-Badge,et al.  Follistatin modulates a BMP autoregulatory loop to control the size and patterning of sensory domains in the developing tongue , 2009, Development.

[8]  Shahab M. Danesh,et al.  BMP and BMP receptor expression during murine organogenesis. , 2009, Gene expression patterns : GEP.

[9]  Benoît Ghaye,et al.  Congenital abnormalities of intrathoracic airways. , 2009, Radiologic clinics of North America.

[10]  R. Mayor,et al.  Differential requirements of BMP and Wnt signalling during gastrulation and neurulation define two steps in neural crest induction , 2009, Development.

[11]  P. Tomà,et al.  Recurrent severe lower respiratory tract infections in a child with abnormal tracheal morphology , 2009, Pediatric pulmonology.

[12]  H. Lehrach,et al.  Control of early fate decisions in human ES cells by distinct states of TGFbeta pathway activity. , 2008, Stem cells and development.

[13]  N. Manley,et al.  Bmp4 is required for tracheal formation: a novel mouse model for tracheal agenesis. , 2008, Developmental Biology.

[14]  D. Warburton,et al.  Prenatal lung epithelial cell-specific abrogation of Alk3-bone morphogenetic protein signaling causes neonatal respiratory distress by disrupting distal airway formation. , 2008, The American journal of pathology.

[15]  B. Hogan,et al.  Multiple dose-dependent roles for Sox2 in the patterning and differentiation of anterior foregut endoderm , 2007, Development.

[16]  T. Desai,et al.  Inhibition of Tgfβ signaling by endogenous retinoic acid is essential for primary lung bud induction , 2007, Development.

[17]  P. ten Dijke,et al.  Aberrant Bmp signaling and notochord delamination in the pathogenesis of esophageal atresia , 2007, Developmental dynamics : an official publication of the American Association of Anatomists.

[18]  C. Stern.  Neural induction: 10 years on since the 'default model'. , 2006, Current opinion in cell biology.

[19]  Fletcher Black,et al.  Sonic the Hedgehog , 2006 .

[20]  J. Klingensmith,et al.  Morphogenesis of the trachea and esophagus: current players and new roles for noggin and Bmps. , 2006, Differentiation; research in biological diversity.

[21]  K. Heimann,et al.  Three new cases of congenital agenesis of the trachea , 2006, European Journal of Pediatrics.

[22]  J. Lü,et al.  Regulation of early lung morphogenesis: questions, facts and controversies , 2006, Development.

[23]  T. Oliver,et al.  Evidence that autocrine signaling through Bmpr1a regulates the proliferation, survival and morphogenetic behavior of distal lung epithelial cells. , 2006, Developmental biology.

[24]  Michael T. McManus,et al.  Dicer function is essential for lung epithelium morphogenesis , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[25]  H. Kondoh,et al.  Convergence of Wnt and FGF signals in the genesis of posterior neural plate through activation of the Sox2 enhancer N-1 , 2005, Development.

[26]  H. Brunner,et al.  Genetic players in esophageal atresia and tracheoesophageal fistula. , 2005, Current opinion in genetics & development.

[27]  J. Wells,et al.  Different thresholds of fibroblast growth factors pattern the ventral foregut into liver and lung , 2004, Development.

[28]  C. Stern,et al.  Neural induction requires BMP inhibition only as a late step, and involves signals other than FGF and Wnt antagonists , 2004, Development.

[29]  C. Tabin,et al.  Evidence for an Expansion-Based Temporal Shh Gradient in Specifying Vertebrate Digit Identities , 2004, Cell.

[30]  J. Algren,et al.  Tracheal agenesis: a rare disease with unique airway considerations. , 2003, Anesthesia and analgesia.

[31]  E. Olson,et al.  Conditional inactivation of FGF receptor 2 reveals an essential role for FGF signaling in the regulation of osteoblast function and bone growth , 2003, Development.

[32]  B. Hogan,et al.  Tissue interactions pattern the mesenchyme of the embryonic mouse lung. , 2003, Developmental biology.

[33]  H. Kondoh,et al.  Functional analysis of chicken Sox2 enhancers highlights an array of diverse regulatory elements that are conserved in mammals. , 2003, Developmental cell.

[34]  Susan E. Wert,et al.  Early restriction of peripheral and proximal cell lineages during formation of the lung , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[35]  Nicole Firnberg,et al.  FGF signaling regulates expression of Tbx2, Erm, Pea3, and Pax3 in the early nasal region. , 2002, Developmental biology.

[36]  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.

[37]  R. Behringer,et al.  Generation of Bmpr/Alk3 conditional knockout mice , 2002, Genesis.

[38]  T. Momoi,et al.  Induction of bud formation of embryonic mouse tracheal epithelium by fibroblast growth factor plus transferrin in mesenchyme‐free culture , 2001, Developmental dynamics : an official publication of the American Association of Anatomists.

[39]  A. McMahon,et al.  Inactivation of the beta-catenin gene by Wnt1-Cre-mediated deletion results in dramatic brain malformation and failure of craniofacial development. , 2001, Development.

[40]  B. Hogan,et al.  Bmp4 and Fgf10 play opposing roles during lung bud morphogenesis. , 2000, Development.

[41]  David Warburton,et al.  The molecular basis of lung morphogenesis , 2000, Mechanisms of Development.

[42]  K. Lyons,et al.  The type I BMP receptor BMPRIB is required for chondrogenesis in the mouse limb. , 2000, Development.

[43]  I. Mason,et al.  Differential Display of Genes Expressed at the Midbrain – Hindbrain Junction Identifies sprouty2: An FGF8-Inducible Member of a Family of Intracellular FGF Antagonists , 2000, Molecular and Cellular Neuroscience.

[44]  M. Taketo,et al.  Intestinal polyposis in mice with a dominant stable mutation of the β‐catenin gene , 1999, The EMBO journal.

[45]  R. Haffner-Krausz,et al.  Fgfr2 is required for limb outgrowth and lung-branching morphogenesis. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[46]  B. Hogan,et al.  Bmp signaling regulates proximal-distal differentiation of endoderm in mouse lung development. , 1999, Development.

[47]  P. Minoo,et al.  Defects in tracheoesophageal and lung morphogenesis in Nkx2.1(-/-) mouse embryos. , 1999, Developmental biology.

[48]  Jian-ming Li,et al.  Smad3-Smad4 and AP-1 Complexes Synergize in Transcriptional Activation of the c-Jun Promoter by Transforming Growth Factor β , 1999, Molecular and Cellular Biology.

[49]  B. Hogan,et al.  BMP4 is essential for lens induction in the mouse embryo. , 1998, Genes & development.

[50]  D. Danilenko,et al.  Fgf-10 is required for both limb and lung development and exhibits striking functional similarity to Drosophila branchless. , 1998, Genes & development.

[51]  H. Westphal,et al.  Sonic hedgehog is essential to foregut development , 1998, Nature Genetics.

[52]  M. Whitman.  Smads and early developmental signaling by the TGFbeta superfamily. , 1998, Genes & development.

[53]  B. Hogan,et al.  Fibroblast growth factor 10 (FGF10) and branching morphogenesis in the embryonic mouse lung. , 1997, Development.

[54]  R. Balling,et al.  Antagonistic Interactions between FGF and BMP Signaling Pathways: A Mechanism for Positioning the Sites of Tooth Formation , 1997, Cell.

[55]  Jeffrey L. Wrana,et al.  Mechanism of activation of the TGF-β receptor , 1994, Nature.

[56]  R. Lauro,et al.  The transcription factor TTF-1 is expressed at the onset of thyroid and lung morphogenesis and in restricted regions of the foetal brain. , 1991, Development.

[57]  Y. Mishina,et al.  BMP receptor ALK3 controls collecting system development. , 2008, Journal of the American Society of Nephrology : JASN.

[58]  Nobuyuki Itoh,et al.  Fgf10 is essential for limb and lung formation , 1999, Nature Genetics.

[59]  Jian-ming Li,et al.  Smad 3-Smad 4 and AP-1 Complexes Synergize in Transcriptional Activation of the c-Jun Promoter by Transforming Growth Factor b , 1999 .

[60]  K. Miyazono,et al.  TGF-beta signalling from cell membrane to nucleus through SMAD proteins. , 1997, Nature.

[61]  B. Hogan,et al.  Fibroblast Growth Factor 10 ( FGF 10 ) and branching morphogenesis in the embryonic mouse lung , 1997 .

[62]  R Wieser,et al.  Mechanism of activation of the TGF-beta receptor. , 1994, Nature.

[63]  J. Evans,et al.  Aberrant bronchi and cardiovascular anomalies. , 1990, American journal of medical genetics.

[64]  J. Thiery,et al.  † Author for correspondence , 1693 .