title: Sall4-Gli3 system in early limb progenitors is essential for the development of limb skeletal elements.
abstract: Limb skeletal elements originate from the limb progenitor cells, which undergo expansion and patterning to develop each skeletal element. Posterior-distal skeletal elements, such as the ulna/fibula and posterior digits develop in a Sonic hedgehog (Shh)-dependent manner. However, it is poorly understood how anterior-proximal elements, such as the humerus/femur, the radius/tibia and the anterior digits, are developed. Here we show that the zinc finger factors Sall4 and Gli3 cooperate for proper development of the anterior-proximal skeletal elements and also function upstream of Shh-dependent posterior skeletal element development. Conditional inactivation of Sall4 in the mesoderm before limb outgrowth caused severe defects in the anterior-proximal skeletal elements in the hindlimb. We found that Gli3 expression is reduced in Sall4 mutant hindlimbs, but not in forelimbs. This reduction caused posteriorization of nascent hindlimb buds, which is correlated with a loss of anterior digits. In proximal development, Sall4 integrates Gli3 and the Plzf-Hox system, in addition to proliferative expansion of cells in the mesenchymal core of nascent hindlimb buds. Whereas forelimbs developed normally in Sall4 mutants, further genetic analysis identified that the Sall4-Gli3 system is a common regulator of the early limb progenitor cells in both forelimbs and hindlimbs. The Sall4-Gli3 system also functions upstream of the Shh-expressing ZPA and the Fgf8-expressing AER in fore- and hindlimbs. Therefore, our study identified a critical role of the Sall4-Gli3 system at the early steps of limb development for proper development of the appendicular skeletal elements.
authors.affiliation: Department of Genetics, Cell Biology and Development, Stem Cell Institute.
authors.forename: Ryutaro
authors.initials: R
authors.lastname: Akiyama
authors.affiliation: Department of Genetics, Cell Biology and Development, Stem Cell Institute.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Kawakami
authors.affiliation: Department of Genetics, Cell Biology and Development.
authors.forename: Julia
authors.initials: J
authors.lastname: Wong
authors.affiliation: Health Research Institute, National Institute of Advanced Industrial Science and Technology, Ikeda, Osaka 563-8577, Japan; and.
authors.forename: Isao
authors.initials: I
authors.lastname: Oishi
authors.affiliation: Department of Kidney Development, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto 860-0811, Japan.
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Nishinakamura
authors.affiliation: Department of Genetics, Cell Biology and Development, Stem Cell Institute, Developmental Biology Center, and Lillehei Heart Institute, University of Minnesota, Minneapolis, MN 55455; kawak005@umn.edu.
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Kawakami
mesh_terms: D000818:Animals; D019521:Body Patterning; D001842:Bone and Bones / Q000196:embryology* / Q000378:metabolism; D049109:Cell Proliferation; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004843:Epistasis, Genetic; D005552:Forelimb / Q000196:embryology* / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D057809:HEK293 Cells; D006614:Hindlimb / Q000196:embryology* / Q000378:metabolism; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism*; D018878:Limb Buds / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D000075722:Promyelocytic Leukemia Zinc Finger Protein; D015398:Signal Transduction; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000074290:Zinc Finger Protein Gli3
chemical_list: D004268:DNA-Binding Proteins; C465571:Gli3 protein, mouse; D018398:Homeodomain Proteins; C501599:Irx3 protein, mouse; C501601:Irx5 protein, mouse; D051741:Kruppel-Like Transcription Factors; D009419:Nerve Tissue Proteins; D000075722:Promyelocytic Leukemia Zinc Finger Protein; C509167:Sall4 protein, mouse; D014157:Transcription Factors; C513267:Zbtb16 protein, mouse; D000074290:Zinc Finger Protein Gli3
keywords: Gli3; Plzf-Hox; Sall4; appendicular skeletal elements; limb progenitors
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