Orofacial clefts are one of the most common birth defects in the U.S., occurring in 1/750 live births. The lifetime cost for medical treatment, educational services and lost productivity averages more than $100,000 per affected person. While the majority of orofacial clefts result in cleft lip with or without cleft palate (CL/P), a small percentage results in oblique facial clefts (ObFC) that extend from the oral cavity to the eye. Although less common, insights into the cellular mechanism of ObFC - first definitively classified by Paul Tessier in 1976 - have remained elusive. We have identified two de novo occurrences of SPECC1L mutations in patients with ObFC. Our studies in zebrafish and fly provide significant insight into SPECC1L function, which thus far had remained unstudied with no scientific publications. Knockdown of a previously uncharacterized zebrafish SPECC1L homolog perturbs cranial neural crest (CNC) and results in a dramafic loss of facial structures, thus extending SPECC1L function in facial morphogenesis to other vertebrates. In addition, knockdown of the sole uncharacterized Drosophila ortholog phenocopies - to an extraordinary extent - known fly mutants in the integrin-signaling pathway that exhibit cell adhesion and migration defects. Furthermore, our cellular and molecular analyses show that SPECC1L is a novel cytoskeletal cross-linking protein that interacts with both the microtubule and actin cytoskeletons. Transient expression of SPECC1LGFP stabilizes a subset of microtubules, while SPECC1L knockdown causes defective actin cytoskeleton reorganization and impairs cell adhesion and migration. Together with mouse Speed I expression in the developing facial prominences, these results begin to explain how human ObFC can arise following SPECC1L deficiency.
The aim of this proposal is to develop a mouse model to test the pathogenetic mechanism of SPECC1L deficiency in mammalian facial morphogenesis (Aim 1) and to precisely define the cellular (Aim 2) and molecular (Aim 3) role of SPECC1L in CNC cell migration and specification of facial structures.

Public Health Relevance

Insights into the cellular and molecular mechanism of oblique facial clefts (ObFC) - that extend from the oral cavity to the eye - have remained elusive. We have identified the first gene, SPECC1L, mutated in patients with ObFC and this proposal aims to define the cellular and molecular role of SPECC1L in mammalian facial morphogenesis using a mouse model.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Exploratory Grants (P20)
Project #
5P20GM104936-07
Application #
8534223
Study Section
Special Emphasis Panel (ZRR1-RI-B)
Project Start
Project End
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
7
Fiscal Year
2013
Total Cost
$218,572
Indirect Cost
$73,822
Name
University of Kansas
Department
Type
DUNS #
016060860
City
Kansas City
State
KS
Country
United States
Zip Code
66160
Wang, Huizhen; Luo, Jinping; Carlton, Carol et al. (2017) Sperm-oocyte contact induces outside-in signaling via PYK2 activation. Dev Biol 428:52-62
Padró, Mercè; Louie, Raymond J; Lananna, Brian V et al. (2017) Genome-independent hypoxic repression of estrogen receptor alpha in breast cancer cells. BMC Cancer 17:203
New, Jacob; Arnold, Levi; Ananth, Megha et al. (2017) Secretory Autophagy in Cancer-Associated Fibroblasts Promotes Head and Neck Cancer Progression and Offers a Novel Therapeutic Target. Cancer Res 77:6679-6691
Rogers, Robert S; Tungtur, Sudheer; Tanaka, Tomohiro et al. (2017) Impaired Mitophagy Plays a Role in Denervation of Neuromuscular Junctions in ALS Mice. Front Neurosci 11:473
Lui, Asona J; Geanes, Eric S; Ogony, Joshua et al. (2017) IFITM1 suppression blocks proliferation and invasion of aromatase inhibitor-resistant breast cancer in vivo by JAK/STAT-mediated induction of p21. Cancer Lett 399:29-43
Tan, Ee Phie; Duncan, Francesca E; Slawson, Chad (2017) The sweet side of the cell cycle. Biochem Soc Trans 45:313-322
Wilson, C; Qiu, L; Hong, Y et al. (2017) The histone demethylase KDM4B regulates peritoneal seeding of ovarian cancer. Oncogene 36:2565-2576
Chen, Lei; Zhao, Lin; Samanta, Anweshan et al. (2017) STAT3 balances myocyte hypertrophy vis-à-vis autophagy in response to Angiotensin II by modulating the AMPK?/mTOR axis. PLoS One 12:e0179835
Jasti, Susmita; Farahbakhsh, Mina; Nguyen, Sean et al. (2017) Immune response to a model shared placenta/tumor-associated antigen reduces cancer risk in parous mice. Biol Reprod 96:134-144
Samanta, Saheli; Rajasingh, Sheeja; Cao, Thuy et al. (2017) Epigenetic dysfunctional diseases and therapy for infection and inflammation. Biochim Biophys Acta 1863:518-528

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