title: Formin1 disruption confers oligodactylism and alters Bmp signaling.
abstract: Proper limb development requires concerted communication between cells within the developing limb bud. Several molecules have been identified which contribute to the formation of a circuitry loop consisting in large part of secreted proteins. The intracellular actin nucleator, Formin 1 (Fmn1), has previously been implicated in limb development, but questions remain after the identification of a Gremlin transcriptional enhancer within the 3' end of the Fmn 1 locus. To resolve this issue, a knockout mouse devoid of Fmn1 protein was created and characterized. The mice exhibit a reduction of digit number to four, a deformed posterior metatarsal, phalangeal soft tissue fusion as well as the absence of a fibula to 100% penetrance in the FVB genetic background. Importantly, this mutant allele does not genetically disrupt the characterized Gremlin enhancer, and indeed Gremlin RNA expression is upregulated at the 35 somite stage of development. Our data reveal increased Bone Morphogenetic Protein (Bmp) activity in mice which carry a disruption in Fmn1, as evidenced by upregulation of Msx1 and a decrease in Fgf4 within the apical ectodermal ridge. Additionally, these studies show enhanced activity downstream of the Bmp receptor in cells where Fmn1 is perturbed, suggesting a role for Fmn1 in repression of Bmp signaling.
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Fen
authors.initials: F
authors.lastname: Zhou
authors.forename: Philip
authors.initials: P
authors.lastname: Leder
authors.forename: Aimée
authors.initials: A
authors.lastname: Zuniga
authors.forename: Markus
authors.initials: M
authors.lastname: Dettenhofer
mesh_terms: D000818:Animals; D052004:Bone Morphogenetic Protein Receptors / Q000235:genetics / Q000378:metabolism; D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D005121:Extremities / Q000196:embryology; D005326:Fetal Proteins / Q000235:genetics* / Q000378:metabolism; D000080865:Formins; D018507:Gene Expression Regulation, Developmental; D020868:Gene Silencing; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D017880:Limb Deformities, Congenital / Q000196:embryology / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000235:genetics* / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D015854:Up-Regulation; D016207:Cytokines
chemical_list: D052004:Bone Morphogenetic Protein Receptors; D019485:Bone Morphogenetic Proteins; D005326:Fetal Proteins; D000080865:Formins; D036341:Intercellular Signaling Peptides and Proteins; D008840:Microfilament Proteins; D009687:Nuclear Proteins; C113178:Grem1 protein, mouse; D016207:Cytokines