title: SPECC1L deficiency results in increased adherens junction stability and reduced cranial neural crest cell delamination.
abstract: Cranial neural crest cells (CNCCs) delaminate from embryonic neural folds and migrate to pharyngeal arches, which give rise to most mid-facial structures. CNCC dysfunction plays a prominent role in the etiology of orofacial clefts, a frequent birth malformation. Heterozygous mutations in SPECC1L have been identified in patients with atypical and syndromic clefts. Here, we report that in SPECC1L-knockdown cultured cells, staining of canonical adherens junction (AJ) components, β-catenin and E-cadherin, was increased, and electron micrographs revealed an apico-basal diffusion of AJs. To understand the role of SPECC1L in craniofacial morphogenesis, we generated a mouse model of Specc1l deficiency. Homozygous mutants were embryonic lethal and showed impaired neural tube closure and CNCC delamination. Staining of AJ proteins was increased in the mutant neural folds. This AJ defect is consistent with impaired CNCC delamination, which requires AJ dissolution. Further, PI3K-AKT signaling was reduced and apoptosis was increased in Specc1l mutants. In vitro, moderate inhibition of PI3K-AKT signaling in wildtype cells was sufficient to cause AJ alterations. Importantly, AJ changes induced by SPECC1L-knockdown were rescued by activating the PI3K-AKT pathway. Together, these data indicate SPECC1L as a novel modulator of PI3K-AKT signaling and AJ biology, required for neural tube closure and CNCC delamination.
authors.affiliation: Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, KS, USA.
authors.forename: Nathan R
authors.initials: NR
authors.lastname: Wilson
authors.affiliation: Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, KS, USA.
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Olm-Shipman
authors.affiliation: Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, KS, USA.
authors.forename: Diana S
authors.initials: DS
authors.lastname: Acevedo
authors.affiliation: Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, KS, USA.
authors.forename: Kanagaraj
authors.initials: K
authors.lastname: Palaniyandi
authors.affiliation: Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, KS, USA.
authors.forename: Everett G
authors.initials: EG
authors.lastname: Hall
authors.affiliation: Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, KS, USA.
authors.forename: Edina
authors.initials: E
authors.lastname: Kosa
authors.affiliation: Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, KS, USA.
authors.forename: Kelly M
authors.initials: KM
authors.lastname: Stumpff
authors.affiliation: Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, KS, USA.
authors.forename: Guerin J
authors.initials: GJ
authors.lastname: Smith
authors.affiliation: Department of Biochemistry, Midwestern University, Downers Grove, IL, USA.
authors.forename: Lenore
authors.initials: L
authors.lastname: Pitstick
authors.affiliation: Center for Regenerative Medicine, Division of Plastic and Reconstructive Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Eric C
authors.initials: EC
authors.lastname: Liao
authors.affiliation: Department of Biochemistry, Midwestern University, Downers Grove, IL, USA.
authors.forename: Bryan C
authors.initials: BC
authors.lastname: Bjork
authors.affiliation: Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, KS, USA.
authors.forename: Andras
authors.initials: A
authors.lastname: Czirok
authors.affiliation: Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, KS, USA.
authors.forename: Irfan
authors.initials: I
authors.lastname: Saadi
mesh_terms: D022005:Adherens Junctions / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D015415:Biomarkers; D015815:Cell Adhesion Molecules / Q000378:metabolism; D019070:Cell Lineage / Q000235:genetics; D015870:Gene Expression; D055786:Gene Knockout Techniques; D006801:Humans; D051379:Mice; D008954:Models, Biological; D009154:Mutation; D009432:Neural Crest / Q000196:embryology* / Q000378:metabolism*; D009436:Neural Tube Defects / Q000235:genetics / Q000473:pathology; D010641:Phenotype; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010750:Phosphoproteins / Q000172:deficiency*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D000096985:Calponins
chemical_list: D015415:Biomarkers; D015815:Cell Adhesion Molecules; D019869:Phosphatidylinositol 3-Kinases; D010750:Phosphoproteins; D051057:Proto-Oncogene Proteins c-akt; C558855:SPECC1L protein, human; D000096985:Calponins