Research
Overview
Craniofacial malformations afflict about 5% of all infants born in the United States and comprise approximately one-third of all birth defects. While a number of contributory genes have been identified, they account for only a subset of cases at best. Thus, there is continued need to identify additional genes and to understand underlying pathogenetic mechanisms. We are currently investigating the role of a novel cytoskeletal protein, SPECC1L, in craniofacial morphogenesis and malformation.
To explore the role of SPECC1L, we are using four broad approaches: 1) Human Genetics – we continue to collaborate with clinicians nationally to identify SPECC1L mutations in patients with syndromic and isolated orofacial clefting [Saadi, 2011; Kruszka, 2015]. 2) Mouse Models – we have now generated an allelic series of Specc1l mutants, including knockout, hypomorphic, and point mutants. These alleles allow us to vary Specc1l dosage, which results in an array of phenotypes, including embryonic lethality, cleft palate, exencephaly, hydrocephalus and behavioral deficits. 3) Cell Biology – we have shown that SPECC1L regulates the density of cell-cell contacts in pre-migratory neural crest cells resulting in defective delamination in severe mutants [Wilson, 2016]. We are using live-cell imaging to show that SPECC1L also regulates cell-cell communication required for collective migration of neural crest cells in hypomorphic and point mutants. 4) Molecular Biology – we have shown that SPECC1L is a novel regulator of PI3K-AKT signaling. We are now using RNA-seq and protein-protein interactions to show how SPECC1L regulates the stability of AKT and other signaling molecules.
Understanding the role of SPECC1L will provide i) valuable insights into modulation of cell-cell contacts and cell adhesion during craniofacial morphogenesis, ii) a novel network of genes that may be involved in craniofacial malformation, and iii) potential therapeutic targets for orofacial clefting.
- Alkuraya, F., S, Saadi, I, Lund, J., J, Turbe-Doan, A, Morton, C., C, Maas, R., L. 2006. SUMO1 haploinsufficiency leads to cleft lip and palate.. Science (New York, N.Y.), 313 (5794), 1751
- Lachke, S., A, Alkuraya, F., S, Kneeland, S., C, Ohn, T, Aboukhalil, A, Howell, G., R, Saadi, I, Cavallesco, R, Yue, Y, Tsai, A., C, Nair, K., S, Cosma, M., I, Smith, R., S, Hodges, E, Alfadhli, S., M, Al-Hajeri, A, Shamseldin, H., E, Behbehani, A, Hannon, G., J, Bulyk, M., L, Drack, A., V, Anderson, P., J, John, S., W, Maas, R., L. 2011. Mutations in the RNA granule component TDRD7 cause cataract and glaucoma.. Science (New York, N.Y.), 331 (6024), 1571-6
- Saadi, I, Alkuraya, F., S, Gisselbrecht, S., S, Goessling, W, Cavallesco, R, Turbe-Doan, A, Petrin, A., L, Harris, J, Siddiqui, U, Grix, Jr, A., W, Hove, H., D, Leboulch, P, Glover, T., W, Morton, C., C, Richieri-Costa, A, Murray, J., C, Erickson, R., P, Maas, R., L. 2011. Deficiency of the cytoskeletal protein SPECC1L leads to oblique facial clefting.. American journal of human genetics, 89 (1), 44-55
- Saadi, I, Das, P, Zhao, M, Raj, L, Ruspita, I, Xia, Y, Papaioannou, V., E, Bei, M. 2013. Msx1 and Tbx2 antagonistically regulate Bmp4 expression during the bud-to-cap stage transition in tooth development.. Development (Cambridge, England), 140 (13), 2697-702
- Dasouki, M., J, Rafi, S., K, Olm-Shipman, A., J, Wilson, N., R, Abhyankar, S, Ganter, B, Furness, L., M, Fang, J, Calado, R., T, Saadi, I. 2013. Exome sequencing reveals a thrombopoietin ligand mutation in a Micronesian family with autosomal recessive aplastic anemia.. Blood, 122 (20), 3440-9
- Wilson, N., R, Olm-Shipman, A., J, Acevedo, D., S, Palaniyandi, K, Hall, E., G, Kosa, E, Stumpff, K., M, Smith, G., J, Pitstick, L, Liao, E., C, Bjork, B., C, Czirok, A, Saadi, I. 2016. SPECC1L deficiency results in increased adherens junction stability and reduced cranial neural crest cell delamination.. Scientific reports, 6, 17735
- Hall, E., G, Wenger, L., W, Wilson, N., R, Undurty-Akella, S., S, Standley, J, Augustine-Akpan, E., A, Kousa, Y., A, Acevedo, D., S, Goering, J., P, Pitstick, L, Natsume, N, Paroya, S., M, Busch, T., D, Ito, M, Mori, A, Imura, H, Schultz-Rogers, L., E, Klee, E., W, Babovic-Vuksanovic, D, Kroc, S., A, Adeyemo, W., L, Eshete, M., A, Bjork, B., C, Suzuki, S, Murray, J., C, Schutte, B., C, Butali, A, Saadi, I. 2020. SPECC1L regulates palate development downstream of IRF6. Human Molecular Genetics, 29 (5), 845-858
- Goering, J., P, Wenger, L., W, Stetsiv, M, Moedritzer, M, Hall, E., G, Isai, D., G, Jack, B., M, Umar, Z, Rickabaugh, M., K, Czirok, A, Saadi, I. 2022. In-frame deletion of SPECC1L microtubule association domain results in gain-of-function phenotypes affecting embryonic tissue movement and fusion events.. Human molecular genetics, 31 (1), 18-31
