title: Combined deficiencies of Msx1 and Msx2 cause impaired patterning and survival of the cranial neural crest.
abstract: The neural crest is a multipotent, migratory cell population that contributes to a variety of tissues and organs during vertebrate embryogenesis. Here, we focus on the function of Msx1 and Msx2, homeobox genes implicated in several disorders affecting craniofacial development in humans. We show that Msx1/2 mutants exhibit profound deficiencies in the development of structures derived from the cranial and cardiac neural crest. These include hypoplastic and mispatterned cranial ganglia, dysmorphogenesis of pharyngeal arch derivatives and abnormal organization of conotruncal structures in the developing heart. The expression of the neural crest markers Ap-2alpha, Sox10 and cadherin 6 (cdh6) in Msx1/2 mutants revealed an apparent retardation in the migration of subpopulations of preotic and postotic neural crest cells, and a disorganization of neural crest cells paralleling patterning defects in cranial nerves. In addition, normally distinct subpopulations of migrating crest underwent mixing. The expression of the hindbrain markers Krox20 and Epha4 was altered in Msx1/2 mutants, suggesting that defects in neural crest populations may result, in part, from defects in rhombomere identity. Msx1/2 mutants also exhibited increased Bmp4 expression in migratory cranial neural crest and pharyngeal arches. Finally, proliferation of neural crest-derived mesenchyme was unchanged, but the number of apoptotic cells was increased substantially in neural crest-derived cells that contribute to the cranial ganglia and the first pharyngeal arch. This increase in apoptosis may contribute to the mispatterning of the cranial ganglia and the hypoplasia of the first arch.
authors.affiliation: Department of Biochemistry and Molecular Biology, Norris Cancer Hospital, Keck School of Medicine, University of Southern California, 1441 Eastlake Avenue, Los Angeles, CA 90089, USA.
authors.forename: Mamoru
authors.initials: M
authors.lastname: Ishii
authors.forename: Jun
authors.initials: J
authors.lastname: Han
authors.forename: Hai-Yun
authors.initials: HY
authors.lastname: Yen
authors.forename: Henry M
authors.initials: HM
authors.lastname: Sucov
authors.forename: Yang
authors.initials: Y
authors.lastname: Chai
authors.forename: Robert E
authors.initials: RE
authors.lastname: Maxson
mesh_terms: D000818:Animals; D019521:Body Patterning / Q000235:genetics*; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D018376:Cardiovascular Abnormalities / Q000235:genetics; D002465:Cell Movement / Q000235:genetics; D003433:Crosses, Genetic; D004268:DNA-Binding Proteins / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D051767:Early Growth Response Protein 2 / Q000096:biosynthesis / Q000235:genetics; D018398:Homeodomain Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology; D051957:MSX1 Transcription Factor / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009432:Neural Crest / Q000196:embryology*; D009436:Neural Tube Defects / Q000196:embryology / Q000235:genetics; D036122:Receptor, EphA4 / Q000096:biosynthesis / Q000235:genetics; D012249:Rhombencephalon / Q000196:embryology / Q000378:metabolism; D012886:Skull / Q000002:abnormalities / Q000196:embryology; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics
chemical_list: C525809:BMP4 protein, human; C525810:Bmp4 protein, mouse; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins; D004268:DNA-Binding Proteins; D051767:Early Growth Response Protein 2; C101121:HOXB1 homeodomain protein; D018398:Homeodomain Proteins; C489520:Hoxd4 protein, mouse; D051957:MSX1 Transcription Factor; C084119:MSX2 protein; C484084:Msx1 protein, mouse; D014157:Transcription Factors; D036122:Receptor, EphA4