title: Transcription factors Mesp2 and Paraxis have critical roles in axial musculoskeletal formation.
abstract: Mesp2 and Paraxis are basic helix-loop-helix (bHLH) -type transcription factors coexpressed in the presomitic mesoderm (PSM) and are required for normal somite formation. Here, we show that Mesp2/Paraxis double-null mice exhibit a distinct phenotype unexpected from either Mesp2 or Paraxis single-null mice. In the posterior region of the body, most of the skeletal components of both the vertebral body and neural arches are severely reduced and only a rudimental lamina and ribs remain, indicating a strong genetic interaction in the sclerotomal cell lineage. However, yeast two-hybrid analyses revealed no direct interaction between Mesp2 and Paraxis. The Mesp2/Paraxis double-null embryo has caudalized somites, revealed by expanded Uncx4.1 expression pattern observed in the Mesp2-null embryo, but the expression level of Uncx4.1 was significantly decreased in mature somites, indicative of hypoplasia of lateral sclerotome derivatives. By focusing on vertebral column formation, we found that expressions of Pax1, Nkx3.1, and Bapx1 are regulated by Paraxis and that Pax9 expression was severely affected in the Mesp2/Paraxis double-null embryo. Furthermore, the expression of Pax3, a crucial factor for hypaxial muscle differentiation, is regulated by both Mesp2 and Paraxis in the anteriormost PSM and nascent somite region. The present data strongly suggest that patterning events by bHLH-type transcription factors have deep impacts on regional chondrogenic and myogenic differentiation of somitic cells, mainly by means of control of Pax genes.
authors.affiliation: Cellular & Molecular Toxicology Division, National Institute of Health Sciences, Setagayaku, Tokyo, Japan. yutak@nihs.go.jp
authors.forename: Yu
authors.initials: Y
authors.lastname: Takahashi
authors.forename: Atsuya
authors.initials: A
authors.lastname: Takagi
authors.forename: Shuichi
authors.initials: S
authors.lastname: Hiraoka
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Koseki
authors.forename: Jun
authors.initials: J
authors.lastname: Kanno
authors.forename: Alan
authors.initials: A
authors.lastname: Rawls
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Saga
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D019521:Body Patterning; D002454:Cell Differentiation; D016764:Cell Polarity; D018507:Gene Expression Regulation, Developmental; D053263:Gene Regulatory Networks; D051379:Mice; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000166:cytology / Q000196:embryology* / Q000378:metabolism*; D000072041:PAX3 Transcription Factor; D051764:PAX9 Transcription Factor; D051761:Paired Box Transcription Factors / Q000235:genetics; D011485:Protein Binding; D019170:Somites / Q000166:cytology / Q000201:enzymology / Q000378:metabolism
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D000072041:PAX3 Transcription Factor; D051764:PAX9 Transcription Factor; D051761:Paired Box Transcription Factors; C107407:Mesp2 protein, mouse; C488759:Pax9 protein, mouse; C093234:Tcf15 protein, mouse; C068686:Pax3 protein, mouse; C070835:PAX1 transcription factor