title: An interdigit signalling centre instructs coordinate phalanx-joint formation governed by 5'Hoxd-Gli3 antagonism.
abstract: The number of phalanges and joints are key features of digit 'identity' and are central to limb functionality and evolutionary adaptation. Prior chick work indicated that digit phalanges and their associated joints arise in a different manner than the more sparsely jointed long bones, and their identity is regulated by differential signalling from adjacent interdigits. Currently, there is no genetic evidence for this model, and the molecular mechanisms governing digit joint specification remain poorly understood. Using genetic approaches in mouse, here we show that functional 5'Hoxd-Gli3 antagonism acts indirectly, through Bmp signalling from the interdigital mesenchyme, to regulate specification of joint progenitors, which arise in conjunction with phalangeal precursors at the digit tip. Phalanx number, although co-regulated, can be uncoupled from joint specification. We propose that 5'Hoxd genes and Gli3 are part of an interdigital signalling centre that sets net Bmp signalling levels from different interdigits to coordinately regulate phalanx and joint formation.
authors.affiliation: Cancer and Developmental Biology Laboratory, CCR, NCI, Frederick, Maryland 21702, USA.
authors.forename: Bau-Lin
authors.identifier: 0000-0003-3747-6697
authors.initials: BL
authors.lastname: Huang
authors.affiliation: Cancer and Developmental Biology Laboratory, CCR, NCI, Frederick, Maryland 21702, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Trofka
authors.affiliation: Cancer and Developmental Biology Laboratory, CCR, NCI, Frederick, Maryland 21702, USA.
authors.forename: Aki
authors.initials: A
authors.lastname: Furusawa
authors.affiliation: Department of Molecular Biosciences and Institute for Cellular and Molecular Biology, University of Texas at Austin, Austin, Texas 78712, USA.
authors.forename: Jacqueline L
authors.initials: JL
authors.lastname: Norrie
authors.affiliation: Department of Molecular Biosciences and Institute for Cellular and Molecular Biology, University of Texas at Austin, Austin, Texas 78712, USA.
authors.forename: Adam H
authors.initials: AH
authors.lastname: Rabinowitz
authors.affiliation: Department of Molecular Biosciences and Institute for Cellular and Molecular Biology, University of Texas at Austin, Austin, Texas 78712, USA.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Vokes
authors.affiliation: Department of Pharmacology, Graduate School of Medicine, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Mark Taketo
authors.affiliation: Department of Genetics and Evolution, University of Geneva, Geneva 4 1211, Switzerland.
authors.forename: Jozsef
authors.initials: J
authors.lastname: Zakany
authors.affiliation: Cancer and Developmental Biology Laboratory, CCR, NCI, Frederick, Maryland 21702, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: Mackem
mesh_terms: D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism; D005121:Extremities / Q000196:embryology*; D018628:Gene Dosage; D055879:Gene Knock-In Techniques; D018398:Homeodomain Proteins / Q000502:physiology*; D007596:Joints / Q000196:embryology* / Q000378:metabolism; D051379:Mice; D009419:Nerve Tissue Proteins / Q000502:physiology*; D010641:Phenotype; D000074290:Zinc Finger Protein Gli3 / Q000502:physiology*; D000099176:Noggin Protein
chemical_list: D019485:Bone Morphogenetic Proteins; D002352:Carrier Proteins; D018398:Homeodomain Proteins; D009419:Nerve Tissue Proteins; D000074290:Zinc Finger Protein Gli3; D000099176:Noggin Protein; C465571:Gli3 protein, mouse