title: Sall genes regulate region-specific morphogenesis in the mouse limb by modulating Hox activities.
abstract: The genetic mechanisms that regulate the complex morphogenesis of generating cartilage elements in correct positions with precise shapes during organogenesis, fundamental issues in developmental biology, are still not well understood. By focusing on the developing mouse limb, we confirm the importance of transcription factors encoded by the Sall gene family in proper limb morphogenesis, and further show that they have overlapping activities in regulating regional morphogenesis in the autopod. Sall1/Sall3 double null mutants exhibit a loss of digit1 as well as a loss or fusion of digit2 and digit3, metacarpals and carpals in the autopod. We show that Sall activity affects different pathways, including the Shh signaling pathway, as well as the Hox network. Shh signaling in the mesenchyme is partially impaired in the Sall mutant limbs. Additionally, our data suggest an antagonism between Sall1-Sall3 and Hoxa13-Hoxd13. We demonstrate that expression of Epha3 and Epha4 is downregulated in the Sall1/Sall3 double null mutants, and, conversely, is upregulated in Hoxa13 and Hoxd13 mutants. Moreover, the expression of Sall1 and Sall3 is upregulated in Hoxa13 and Hoxd13 mutants. Furthermore, by using DNA-binding assays, we show that Sall and Hox compete for a target sequence in the Epha4 upstream region. In conjunction with the Shh pathway, the antagonistic interaction between Hoxa13-Hoxd13 and Sall1-Sall3 in the developing limb may contribute to the fine-tuning of local Hox activity that leads to proper morphogenesis of each cartilage element of the vertebrate autopod.
authors.affiliation: Gene Expression Laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Kawakami
authors.forename: Yukako
authors.initials: Y
authors.lastname: Uchiyama
authors.forename: Concepcion
authors.initials: C
authors.lastname: Rodriguez Esteban
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Inenaga
authors.forename: Naoko
authors.initials: N
authors.lastname: Koyano-Nakagawa
authors.forename: Hiroko
authors.initials: H
authors.lastname: Kawakami
authors.forename: Merce
authors.initials: M
authors.lastname: Marti
authors.forename: Marie
authors.initials: M
authors.lastname: Kmita
authors.forename: Paula
authors.initials: P
authors.lastname: Monaghan-Nichols
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Nishinakamura
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: Izpisua Belmonte
mesh_terms: D000818:Animals; D005121:Extremities / Q000196:embryology*; D018507:Gene Expression Regulation, Developmental; D053823:Hedgehog Proteins / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism*; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism; D051379:Mice; D009024:Morphogenesis; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009928:Organ Specificity; D036121:Receptor, EphA3 / Q000378:metabolism; D036122:Receptor, EphA4 / Q000378:metabolism; D015398:Signal Transduction; D020825:T-Box Domain Proteins / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D000074290:Zinc Finger Protein Gli3
chemical_list: C465571:Gli3 protein, mouse; D053823:Hedgehog Proteins; D018398:Homeodomain Proteins; C084118:Hoxd13 protein, mouse; D051741:Kruppel-Like Transcription Factors; D009419:Nerve Tissue Proteins; C491254:Sall1 protein, mouse; C484467:Sall3 protein, mouse; C465570:Shh protein, mouse; D020825:T-Box Domain Proteins; C103172:T-box transcription factor 5; D014157:Transcription Factors; D000074290:Zinc Finger Protein Gli3; C099959:homeobox protein HOXA13; C491717:Epha3 protein, mouse; D036121:Receptor, EphA3; D036122:Receptor, EphA4