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Characterization of SPECC1L Function in Palatogenesis

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Characterization of SPECC1L Function in Palatogenesis Characterization of SPECC1L Function in Palatogenesis By © 2019 Everett Gordon Hall B.A. Biology, Westminster College, Missouri, 2013 Submitted to the graduate degree program in Anatomy and Cell Biology and the Graduate Faculty of the University of Kansas in partial fulfillment of the requirements for the degree of Doctor of Philosophy. ________________________________________ Chair: Dr. Irfan Saadi ________________________________________ Dr. András Czirók ________________________________________ Dr. Brenda Rongish ________________________________________ Dr. Paul Trainor ________________________________________ Dr. Pamela Tran ________________________________________ Dr. Jinxi Wang Date Defended: April 26, 2019 The dissertation committee for Everett Gordon Hall certifies that this is the approved version of the following dissertation: Characterization of SPECC1L Function in Palatogenesis ________________________________________ Chair: Dr. Irfan Saadi Date Approved: May 16, 2019 ii Abstract Orofacial clefts are among the most common congenital birth defects, occurring in as many as 1 in 800 births worldwide. Genetic and environmental factors contribute to the complex etiology of these anomalies. SPECC1L encodes a cytoskeletal protein with roles in adhesion, migration, and cytoskeletal organization. SPECC1L mutations have been identified in patients with atypical clefts, Opitz G/BBB syndrome, and Teebi hypertelorism syndrome. Our lab has previously shown that knockout of Specc1l in mice with gene trap alleles results in early embryonic lethality with defects in neural tube closure and neural crest cell delamination, as well as reduced PI3K-AKT signaling. However, the early lethality phenotype rendered these models incapable of recapitulating the human anomalies. To validate a role for SPECC1L in palatogenesis, we generated additional gene trap and truncation mutant Specc1l alleles. Specc1lgenetrap/truncation compound heterozygote embryos survive to the perinatal period, allowing analysis at later developmental stages. Examination of compound mutant palates revealed a delay in palate elevation, abnormal oral adhesions, and ectopic expression of adherens junction protein β-catenin at the apical surface of oral epithelial periderm cells, as well as a global increase in actin filament staining. We also establish that transcription factor IRF6, which has a causative role in many cases of orofacial clefting, is required for SPECC1L expression in the palate. After establishing a role for SPECC1L in the palatal epithelium, we asked if it also acted in the migration of palatal mesenchyme. Indeed, time-lapse imaging analysis of primary mouse embryonic palatal mesenchyme (MEPM) cells from Specc1lgenetrap/truncation mutant embryos show defects in migration. We also demonstrate that activation of the PI3K-AKT pathway with a small molecule activator improves mutant wound closure speed. Furthermore, random 2-D motility cultures revealed that MEPM cells have attributes of collective migration that are reduced in mutant cells. iii Lastly, we generated a mouse allele with the T397P point mutation, located in the second coiled- coil domain (CCD2) of SPECC1L, that was previously identified in patients with Opitz G/BBB syndrome. Embryos with this allele displayed omphalocele and completely penetrant cleft palate defects that recapitulated the phenotype of patients with SPECC1L mutations. Together, these data identify roles for SPECC1L in palate epithelial integrity and mesenchymal remodeling, and thus firmly establish a requirement for SPECC1L in palatogenesis. iv Table of Contents Abstract ......................................................................................................................................... iii Chapter One: Introduction .......................................................................................................... 1 1.1 Orofacial Clefting ................................................................................................................ 2 1.1.1 Early craniofacial development ...................................................................................... 2 1.1.2 Orofacial clefting in humans .......................................................................................... 2 1.1.3 Investigating the genetic etiology of orofacial clefts ...................................................... 5 1.1.4 Mouse models of orofacial clefting ................................................................................ 6 1.2 Palate Development ............................................................................................................. 8 1.2.1 Neural crest cells ............................................................................................................ 8 1.2.2 Mammalian palatogenesis: Mechanisms of palatal shelf outgrowth ............................ 12 1.2.3 Mammalian palatogenesis: Mechanisms of palatal shelf elevation .............................. 14 1.2.4 Mammalian palatogenesis: Mechanisms of palatal shelf fusion .................................. 18 1.2.5 Mammalian palatogenesis: Mechanisms of palatal shelf ossification and patterning .. 20 1.3 Broader roles of the epithelium: IRF6 network in periderm development and palatogenesis ............................................................................................................................ 22 1.4 Mesenchymal migration and remodeling in palatogenesis ............................................ 27 1.5 SPECC1L in craniofacial development ........................................................................... 32 1.5.1 SPECC1L mutations in human patients with orofacial clefts ...................................... 32 1.5.2 Diverse functions of coiled-coil and calponin homology domain-containing cytoskeletal proteins .............................................................................................................. 35 1.5.3 Cellular analysis of SPECC1L expression ................................................................... 36 1.5.4 Cellular analysis of SPECC1L function ....................................................................... 37 1.5.5 Animal models of SPECC1L deficiency ...................................................................... 39 1.6 Study Significance ............................................................................................................. 42 Chapter Two: SPECC1L regulates palate development downstream of IRF6..................... 44 2.1 Abstract .............................................................................................................................. 45 2.2 Introduction ....................................................................................................................... 46 2.3 Materials and Methods ..................................................................................................... 49 2.3.1 Patient information ....................................................................................................... 49 2.3.2 Generation of Specc1lΔC510 truncation allele ................................................................ 49 2.3.3 Generation of Specc1lcGT gene trap allele .................................................................... 49 v 2.3.4 Histological analysis ..................................................................................................... 51 2.3.5 Immunostaining analysis .............................................................................................. 52 2.3.6 Western blot analysis .................................................................................................... 53 2.3.7 Cell culture and transfection analysis ........................................................................... 53 2.4 Results ................................................................................................................................ 54 2.4.1 Moderate reduction of Specc1l in mouse results in palate elevation defect ................. 54 2.4.2 Specc1lcGT/ΔC510 mutants show ectopic oral adhesions and abnormal periderm ........... 59 2.4.3 Specc1lcGT/ΔC510 mutants show abnormal adherens junction staining in the periderm . 59 2.4.4 SPECC1L expression in the palate is dependent upon IRF6 transcription factor ........ 63 2.4.5 Identification of nonsynonymous SPECC1L coding variants in nsCL/P patients ....... 64 2.4.6 Expression analysis of SPECC1L variants shows reduced acetylation of SPECC1L- associated microtubules ......................................................................................................... 68 2.5 Discussion ........................................................................................................................... 72 Chapter Three: Migration defects in SPECC1L-deficient palatal mesenchyme cells can be rescued by activation of the PI3K-AKT pathway .................................................................... 76 3.1 Abstract .............................................................................................................................. 77 3.2 Introduction ....................................................................................................................... 78 3.3 Materials and Methods ..................................................................................................... 81 3.3.1 U2OS and MEPM cell culture ...................................................................................... 81 3.3.2 Time-lapse
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