title: Transient Inhibition of FGFR2b-ligands signaling leads to irreversible loss of cellular β-catenin organization and signaling in AER during mouse limb development.
abstract: The vertebrate limbs develop through coordinated series of inductive, growth and patterning events. Fibroblast Growth Factor receptor 2b (FGFR2b) signaling controls the induction of the Apical Ectodermal Ridge (AER) but its putative roles in limb outgrowth and patterning, as well as in AER morphology and cell behavior have remained unclear. We have investigated these roles through graded and reversible expression of soluble dominant-negative FGFR2b molecules at various times during mouse limb development, using a doxycycline/transactivator/tet(O)-responsive system. Transient attenuation (≤ 24 hours) of FGFR2b-ligands signaling at E8.5, prior to limb bud induction, leads mostly to the loss or truncation of proximal skeletal elements with less severe impact on distal elements. Attenuation from E9.5 onwards, however, has an irreversible effect on the stability of the AER, resulting in a progressive loss of distal limb skeletal elements. The primary consequences of FGFR2b-ligands attenuation is a transient loss of cell adhesion and down-regulation of P63, β1-integrin and E-cadherin, and a permanent loss of cellular β-catenin organization and WNT signaling within the AER. Combined, these effects lead to the progressive transformation of the AER cells from pluristratified to squamous epithelial-like cells within 24 hours of doxycycline administration. These findings show that FGFR2b-ligands signaling has critical stage-specific roles in maintaining the AER during limb development.
authors.affiliation: Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America ; Developmental Biology and Regenerative Medicine Program, Saban Research Institute of Childrens Hospital Los Angeles, Los Angeles, California, United States of America.
authors.forename: Soula
authors.initials: S
authors.lastname: Danopoulos
authors.forename: Sara
authors.initials: S
authors.lastname: Parsa
authors.forename: Denise
authors.initials: D
authors.lastname: Al Alam
authors.forename: Reza
authors.initials: R
authors.lastname: Tabatabai
authors.forename: Sheryl
authors.initials: S
authors.lastname: Baptista
authors.forename: Caterina
authors.initials: C
authors.lastname: Tiozzo
authors.forename: Gianni
authors.initials: G
authors.lastname: Carraro
authors.forename: Matthew
authors.initials: M
authors.lastname: Wheeler
authors.forename: Guillermo
authors.initials: G
authors.lastname: Barreto
authors.forename: Thomas
authors.initials: T
authors.lastname: Braun
authors.forename: Xiaokun
authors.initials: X
authors.lastname: Li
authors.forename: Mohammad K
authors.initials: MK
authors.lastname: Hajihosseini
authors.forename: Saverio
authors.initials: S
authors.lastname: Bellusci
mesh_terms: D000818:Animals; D002448:Cell Adhesion / Q000502:physiology; D015536:Down-Regulation / Q000502:physiology; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental / Q000502:physiology; D006614:Hindlimb / Q000196:embryology*; D008024:Ligands; D008822:Mice, Transgenic; D038081:Organogenesis / Q000502:physiology*; D010750:Phosphoproteins / Q000096:biosynthesis / Q000235:genetics; D015534:Trans-Activators / Q000096:biosynthesis / Q000235:genetics; D060449:Wnt Signaling Pathway / Q000502:physiology*; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
chemical_list: D008024:Ligands; D010750:Phosphoproteins; D015534:Trans-Activators; C486419:Trp63 protein, mouse; D051176:beta Catenin; C541485:EGFR protein, mouse; D066246:ErbB Receptors