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The apical ectodermal ridge of the mouse model of ectrodactyly Dlx5;Dlx6-/- shows altered stratification and cell polarity, which are restored by exogenous Wnt5a ligand.

ABSTRACT: The congenital malformation split hand/foot (SHFM) is characterized by missing central fingers and dysmorphology or fusion of the remaining ones. Type-1 SHFM is linked to deletions/rearrangements of the DLX5-DLX6 locus and point mutations in the DLX5 gene. The ectrodactyly phenotype is reproduced in mice by the double knockout (DKO) of Dlx5 and Dlx6. During limb development, the apical ectodermal ridge (AER) is a key-signaling center responsible for early proximal-distal growth and patterning. In Dlx5;6 DKO hindlimbs, the central wedge of the AER loses multilayered organization and shows down-regulation of FGF8 and Dlx2. In search for the mechanism, we examined the non-canonical Wnt signaling, considering that Dwnt-5 is a target of distalless in Drosophila and the knockout of Wnt5, Ryk, Ror2 and Vangl2 in the mouse causes severe limb malformations. We found that in Dlx5;6 DKO limbs, the AER expresses lower levels of Wnt5a, shows scattered ?-catenin responsive cells and altered basolateral and planar cell polarity (PCP). The addition of Wnt5a to cultured embryonic limbs restored the expression of AER markers and its stratification. Conversely, the inhibition of the PCP molecule c-jun N-terminal kinase caused a loss of AER marker expression. In vitro, the addition of Wnt5a on mixed primary cultures of embryonic ectoderm and mesenchyme was able to confer re-polarization. We conclude that the Dlx-related ectrodactyly defect is associated with the loss of basoapical and PCP, due to reduced Wnt5a expression and that the restoration of the Wnt5a level is sufficient to partially reverts AER misorganization and dysmorphology.

SUBMITTER: Conte D

PROVIDER: S-EPMC4743692 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature

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The apical ectodermal ridge of the mouse model of ectrodactyly Dlx5;Dlx6-/- shows altered stratification and cell polarity, which are restored by exogenous Wnt5a ligand.

Conte Daniele D Garaffo Giulia G Lo Iacono Nadia N Mantero Stefano S Piccolo Stefano S Cordenonsi Michelangelo M Perez-Morga David D Orecchia Valeria V Poli Valeria V Merlo Giorgio R GR

Human molecular genetics 20151218 4

The congenital malformation split hand/foot (SHFM) is characterized by missing central fingers and dysmorphology or fusion of the remaining ones. Type-1 SHFM is linked to deletions/rearrangements of the DLX5-DLX6 locus and point mutations in the DLX5 gene. The ectrodactyly phenotype is reproduced in mice by the double knockout (DKO) of Dlx5 and Dlx6. During limb development, the apical ectodermal ridge (AER) is a key-signaling center responsible for early proximal-distal growth and patterning. I ...[more]

PMID: 26685160

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Project description:INTRODUCTION:An analysis was made of three different syndromes associated with p63 gene mutations, known as ectrodactyly-ectodermal dysplasia-clefting syndrome (EEC), ankyloblepharon-ectodermal dysplasia clefting syndrome (AEC or Hay-Wells) and Rapp-Hodgkin syndrome (RHS). The postoperative complications associated with their cleft reconstructions were also evaluated. MATERIALS AND METHODS:Extensive demographic information, in particular of the clinical appearances, associated malformations, and the types and complications of the reconstructive surgical procedures, were recorded of these syndromic cases occurring in a database of 3621 facial cleft deformity patients. The data was analyzed using the Microsoft Excel program. RESULTS:A total of 10 (0.28%) cases of p63 associated syndromes were recorded: EEC (6), RHS (3), and AEC (1). The following clinical cleft appearances were noted - EEC = 6: CLA 1 -right side unilateral (female); CLAP 4 - right side (1) + left side (1) unilateral (male + female); bilateral (2) (males); hPsP 1 (female) (divided in 3 Black, 2 White, 1 Indian); RHS = 3: CLAP 2 (White males); hPsP 1 (White female); AEC = 1: CLAP bilateral (White male). Other features of the syndromes were: skin, hand, foot, tooth, hair and nail involvement, and light sensitivity. Postoperative complications included: (i) stenosis of nasal opening, especially after reconstruction of the bilateral cleft lip and the columella lengthening (2 cases), (ii) premaxilla-prolabium fusion (2 cases), (iii) repeated occurrence of oro-nasal fistula in the hard palate (4 cases), and (iv) dysgnathial development of midfacial structures (3 cases). DISCUSSION:Three different p63 associated syndromes (EEC, AEC, and RHS) were diagnosed (0.27% of the total facial cleft deformities database). The majority of the cases presented with a bilateral CLAP in males only. A number of females and males had unilateral CLA. The hPsP-cleft was recorded in females only. The associated ectodermal component most probably had a profoundly negative influence on postoperatively wound healing, which was observed in particular at the nasal openings, the premaxilla sulcus and in the hard palate mucosa. The reconstruction of p63 associated syndromes is a greater challenge than the usual cleft reconstruction to the surgeon.

Dataset Information

The apical ectodermal ridge of the mouse model of ectrodactyly Dlx5;Dlx6-/- shows altered stratification and cell polarity, which are restored by exogenous Wnt5a ligand.

Publications

The apical ectodermal ridge of the mouse model of ectrodactyly Dlx5;Dlx6-/- shows altered stratification and cell polarity, which are restored by exogenous Wnt5a ligand.

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