Meis2 is essential for cranial and cardiac neural crest development

BackgroundTALE-class homeodomain transcription factors Meis and Pbx play important roles in formation of the embryonic brain, eye, heart, cartilage or hematopoiesis. Loss-of-function studies of Pbx1, 2 and 3 and Meis1 documented specific functions in embryogenesis, however, functional studies of Meis2 in mouse are still missing. We have generated a conditional allele of Meis2 in mice and shown that systemic inactivation of the Meis2 gene results in lethality by the embryonic day 14 that is accompanied with hemorrhaging.ResultsWe show that neural crest cells express Meis2 and Meis2-defficient embryos display defects in tissues that are derived from the neural crest, such as an abnormal heart outflow tract with the persistent truncus arteriosus and abnormal cranial nerves. The importance of Meis2 for neural crest cells is further confirmed by means of conditional inactivation of Meis2 using crest-specific AP2α-IRES-Cre mouse. Conditional mutants display perturbed development of the craniofacial skeleton with severe anomalies in cranial bones and cartilages, heart and cranial nerve abnormalities.ConclusionsMeis2-null mice are embryonic lethal. Our results reveal a critical role of Meis2 during cranial and cardiac neural crest cells development in mouse.

[1]  D. Schulte,et al.  Meis2 competes with the Groucho co-repressor Tle4 for binding to Otx2 and specifies tectal fate without induction of a secondary midbrain-hindbrain boundary organizer , 2009, Development.

[2]  羽藤 晋 Functional corneal endothelium derived from corneal stroma stem cells of neural crest origin by retinoic acid and Wnt/β-catenin signaling , 2013 .

[3]  Adam A. Friedman,et al.  Meis homeoproteins directly regulate Pax6 during vertebrate lens morphogenesis. , 2002, Genes & development.

[4]  R. Krumlauf,et al.  Cranial neural crest cells regulate head muscle patterning and differentiation during vertebrate embryogenesis , 2007, Development.

[5]  S. Choe,et al.  Meis cofactors control HDAC and CBP accessibility at Hox-regulated promoters during zebrafish embryogenesis. , 2009, Developmental cell.

[6]  R. Jaenisch,et al.  Transcription factor AP-2 essential for cranial closure and craniofacial development , 1996, Nature.

[7]  H. Okano,et al.  Isolation of Multipotent Neural Crest‐Derived Stem Cells from the Adult Mouse Cornea , 2006, Stem cells.

[8]  Weiguo Feng,et al.  A morpholino‐based screen to identify novel genes involved in craniofacial morphogenesis , 2013, Developmental dynamics : an official publication of the American Association of Anatomists.

[9]  T. Stuhlmiller,et al.  Current perspectives of the signaling pathways directing neural crest induction , 2012, Cellular and Molecular Life Sciences.

[10]  N. Copeland,et al.  Identification of a new family of Pbx-related homeobox genes. , 1996, Oncogene.

[11]  P. Labosky,et al.  Neural crest stem cell multipotency requires Foxd3 to maintain neural potential and repress mesenchymal fates , 2011, Journal of Cell Science.

[12]  J. Thiery,et al.  Cell delamination in the mesencephalic neural fold and its implication for the origin of ectomesenchyme , 2013, Development.

[13]  Benjamin R. Arenkiel,et al.  Ablation of specific expression domains reveals discrete functions of ectoderm- and endoderm-derived FGF8 during cardiovascular and pharyngeal development , 2003, Development.

[14]  R. Pfundt,et al.  Haploinsufficiency of MEIS2 is associated with orofacial clefting and learning disability , 2014, American journal of medical genetics. Part A.

[15]  K. Devriendt,et al.  MEIS2 involvement in cardiac development, cleft palate, and intellectual disability , 2015, American journal of medical genetics. Part A.

[16]  Sean Thomas,et al.  A Temporal Chromatin Signature in Human Embryonic Stem Cells Identifies Regulators of Cardiac Development , 2012, Cell.

[17]  Philippe Soriano Generalized lacZ expression with the ROSA26 Cre reporter strain , 1999, Nature Genetics.

[18]  Michael L. Cleary,et al.  Trimeric Association of Hox and TALE Homeodomain Proteins Mediates Hoxb2 Hindbrain Enhancer Activity , 1999, Molecular and Cellular Biology.

[19]  S. Choe,et al.  Meis3 synergizes with Pbx4 and Hoxb1b in promoting hindbrain fates in the zebrafish. , 2001, Development.

[20]  Atsushi Miyawaki,et al.  Scale: a chemical approach for fluorescence imaging and reconstruction of transparent mouse brain , 2011, Nature Neuroscience.

[21]  Ginés Morata,et al.  Conserved regulation of proximodistal limb axis development by Meis1/Hth , 1999, Nature.

[22]  Wei Chen,et al.  Characterization of a 5.3 Mb deletion in 15q14 by comparative genomic hybridization using a whole genome “tiling path” BAC array in a girl with heart defect, cleft palate, and developmental delay , 2007, American Journal of Medical Genetics. Part A.

[23]  G. Proetzel,et al.  Expression of Meis2, a Knotted‐related murine homeobox gene, indicates a role in the differentiation of the forebrain and the somitic mesoderm , 1997, Developmental dynamics : an official publication of the American Association of Anatomists.

[24]  E. Zackai,et al.  Further evidence for the possible role of MEIS2 in the development of cleft palate and cardiac septum , 2010, American journal of medical genetics. Part A.

[25]  M. Kirby,et al.  Factors controlling cardiac neural crest cell migration , 2010, Cell adhesion & migration.

[26]  A. McMahon,et al.  Neural tube, skeletal and body wall defects in mice lacking transcription factor AP-2 , 1996, Nature.

[27]  C. Sagerström,et al.  Hox regulation of transcription: More complex(es) , 2014, Developmental dynamics : an official publication of the American Association of Anatomists.

[28]  K. Stankunas,et al.  Pbx/Meis Deficiencies Demonstrate Multigenetic Origins of Congenital Heart Disease , 2008, Circulation research.

[29]  N. Copeland,et al.  Hematopoietic, angiogenic and eye defects in Meis1 mutant animals , 2004, The EMBO journal.

[30]  J. I. Izpisúa Belmonte,et al.  Control of vertebrate limb outgrowth by the proximal factor Meis2 and distal antagonism of BMPs by Gremlin. , 1999, Molecular cell.

[31]  S. Choe,et al.  Meis family proteins are required for hindbrain development in the zebrafish. , 2002, Development.

[32]  A. Waskiewicz,et al.  Zebrafish Meis functions to stabilize Pbx proteins and regulate hindbrain patterning. , 2001, Development.

[33]  K. Stankunas,et al.  Pbx1 functions in distinct regulatory networks to pattern the great arteries and cardiac outflow tract , 2008, Development.

[34]  T. Kunz,et al.  Compound developmental eye disorders following inactivation of TGFβ signaling in neural-crest stem cells , 2005, Journal of biology.

[35]  S. Tapscott,et al.  A conserved motif N-terminal to the DNA-binding domains of myogenic bHLH transcription factors mediates cooperative DNA binding with pbx-Meis1/Prep1. , 1999, Nucleic acids research.

[36]  Jun Wang,et al.  Bmp signaling represses Vegfa to promote outflow tract cushion development , 2013, Development.

[37]  Marianne Bronner-Fraser,et al.  A gene regulatory network orchestrates neural crest formation , 2008, Nature Reviews Molecular Cell Biology.

[38]  N. Green,et al.  PBX and MEIS as Non-DNA-Binding Partners in Trimeric Complexes with HOX Proteins , 1999, Molecular and Cellular Biology.

[39]  D. Schulte,et al.  Evidence for an evolutionary conserved role of homothorax/Meis1/2 during vertebrate retina development , 2008, Development.

[40]  C. Martínez-A,et al.  The homeodomain protein Meis1 is essential for definitive hematopoiesis and vascular patterning in the mouse embryo. , 2005, Developmental biology.

[41]  J. Seidman,et al.  Spatial transcriptional profile of the chick and mouse endocardial cushions identify novel regulators of endocardial EMT in vitro. , 2013, Journal of molecular and cellular cardiology.

[42]  M. Bronner,et al.  Development and evolution of the neural crest: an overview. , 2012, Developmental biology.

[43]  F. Rijli,et al.  Cranial neural crest and the building of the vertebrate head , 2003, Nature Reviews Neuroscience.

[44]  Ansuman T. Satpathy,et al.  Dual actions of Meis1 inhibit erythroid progenitor development and sustain general hematopoietic cell proliferation. , 2012, Blood.

[45]  F. Rijli,et al.  Molecular mechanisms of cranial neural crest cell migration and patterning in craniofacial development , 2010, Development.

[46]  L. Sommer,et al.  Neural crest progenitors and stem cells: from early development to adulthood. , 2012, Developmental biology.

[47]  R. Schwartz,et al.  Pax3 is essential for normal cardiac neural crest morphogenesis but is not required during migration nor outflow tract septation. , 2011, Developmental biology.

[48]  D. Rowitch,et al.  Sox9 is required for determination of the chondrogenic cell lineage in the cranial neural crest , 2003, Proceedings of the National Academy of Sciences of the United States of America.