The mammalian skin epithelium (epidermis) is an ideal model system to study fundamental questions in stem cell and cancer biology. It is accessible; it can be cultured, genetically manipulated and transplanted; and its resident stem cells possess unparalleled regenerative capacity. Our skin, unlike many other organs, undergoes continuous growth and turnover. And unlike other “simple” epithelia, the epidermis is stratified, consisting of many cell layers with specialized functions. In development and homeostasis, progenitors in the skin must balance self-renewal and differentiation programs. We have found that asymmetric cell divisions are a critical mechanism by which skin progenitors maintain this equilibrium. We are interested in studying how this asymmetry is controlled at a molecular level, and how division orientation impacts cell fate choices in normal and neoplastic growth. To facilitate these and other studies in diverse epithelia, we have developed a powerful functional tool, in utero lentiviral RNAi (see figure, below), which allows us to rapidly perform functional studies on any gene in the intact mouse in weeks instead of years. Our broad goal will be to use this technique, in combinations of candidate and screening approaches, to dissect pathways that influence epithelial differentiation.
Beyond studying how division orientation influences epidermal development, we also study the role that the spindle orientation complex plays in other tissues, including the cerebellum and oral epithelia. In addition, we have broad interests in studying the mechanisms that control the formation and maintenance of stratified epithelia in the context of development, stem cell function, and disease. Two particular areas of great interest are head and neck cancers, and cleft lip and palate.
Williams SE and Lough KJ. Cell biology: Pardon the intrusion. Curr Biol 2020 Dec 21; 30(24): R1481-4. doi: 10.1016/j.cub.2020.10.036. PMID: 33352130
Lough KJ, Spitzer DC, Bergman AJ, Wu JJ, Byrd KM, Williams SE. Cleft palate is caused by disruption of the nectin-afadin cell-cell adhesion complex. Development 2020 Jul 13; 147(21):dev.189241. [Special issue on “The Origins and Mechanisms of Developmental Disorders”]. PMID: 32554531
Lough KJ, Byrd KM, Descovich CP, Spitzer DC, Bergman AJ, Beaudoin III GM, Reichardt LF and Williams SE. Telophase correction refines division orientation in stratified epithelia. eLife 2019 Dec 13;8. pii: e49249. PMID: 31833472
Byrd KM, Piehl NC, Patel JH, Huh WJ, Sequeira I, Lough KJ, Wagner BL, Marangoni P, Watt FM, Klein OD, Coffey RJ, Williams SE. Heterogeneity within stratified epithelial stem cell populations maintains the oral mucosa in response to physiological stress. Cell Stem Cell 2019 Dec 5; 25(6): 814-29. PMID: 31809739
Carper MB, Troutman S, Wagner BL, Byrd KM, Selitsky SR, Parag-Sharma K, Henry EC, Li W, Parker JS, Montgomery SA, Cleveland JL, Williams SE, Kissil JL, Hayes DN, Amelio AL. An immunocompetent mouse model of HPV16(+) head and neck squamous cell carcinoma. Cell Reports 2019 Nov 5;29(6):1660-1674.e7. PMID: 31693903
Lough KJ, Byrd KM, Spitzer DC, and Williams SE (2017). Closing the gap: mouse models to study adhesion in secondary palatogenesis. J Dent Res [Special Issue on Orofacial Clefting, Craniofacial and Dental Anomalies] Available online August 17, 2017. PMID: 28817360
Byrd KM, Lough KJ, Patel JH, Descovich CP, Curtis TA and Williams SE (2016). LGN plays distinct roles in oral epithelial stratification, filiform papilla morphogenesis and hair follicle development. Development 143(15): 2803-17. PMID: 27317810 [Selected for Cover, F1000 reviewed]
Williams SE*, Garcia I, Crowther AJ, Stewart A, Li S, Stewart A, Liu H, Lough, KJ, O’Neill S, Veleta K, Oyarzabal EA, Merrill JR, Shi YI and Gershon TR* (2015). Aspm sustains postnatal cerebellar neurogenesis and medulloblastoma growth in mice. Development 142(22): 3921-32. PMID: 26450969 *co-corresponding authors
Williams SE, Ratliff LA, Postiglione MP, Knoblich JA and Fuchs E (2014). Par3-mInsc and Gai3 cooperate to promote oriented epidermal cell divisions through LGN. Nat Cell Biol 16(8): 758-69. PMID: 25016959 [F1000 reviewed]
Williams SE and Fuchs E (2013). Oriented divisions, fate decisions. Curr Opin Cell Biol 25(6):749–758. PMID: 24021274
Williams SE, Beronja S, Pasolli HA and Fuchs E (2011). Asymmetric cell divisions promote Notch-dependent epidermal differentiation. Nature 470: 353-358. PMID: 21331036 [Comment in Nat Rev Genetics 12: 226; F1000 reviewed].
Ezratty E, Stokes N, Chai S, Shah A, Williams SE and Fuchs E (2011). A role for the primary cilium in Notch signaling and epidermal differentiation during skin development. Cell 45: 1129-41. PMID: 21703454
Luxenburg C, Pasolli HA, Williams SE and Fuchs E (2011). Developmental roles for Srf, cortical cytoskeleton and cell shape in epidermal spindle orientation. Nat Cell Biol 13: 203-14. PMID: 21336301 [F1000 reviewed]
Beronja S, Livshits G, Williams SE and Fuchs E (2010). Rapid functional dissection of genetic networks via tissue-specific transduction and RNAi in mouse embryos. Nat Med 16: 821-7. PMID: 20526348
Perez-Moreno M, Song W, Pasolli HA, Williams SE and Fuchs E (2008). Loss of p120 catenin and links to mitotic alterations, inflammation and skin cancer. PNAS 105: 15399-404. PMID: 18809907 [F1000 reviewed]
Williams SE, Grumet M, Colman DR, Henkemeyer M, Mason CA, and Sakurai T (2006). A role for Nr-CAM in the patterning of binocular visual pathways. Neuron 50: 535-47. PMID: 16701205 [Comment in Neuron 50: 519-21]
Williams SE, Mason CA, and Herrera E (2004). The optic chiasm as a midline choice point. Curr Opin Neurobiol 14: 51-60. PMID: 15018938
Williams SE, Mann F, Sakurai T, Erskine L, Wei S, Rossi DJ, Gale N, Holt CE, Mason CA, and Henkemeyer M (2003). Ephrin-B2 and EphB1 mediate retinal axon divergence at the optic chiasm. Neuron 39: 919-935. PMID: 12971893 [Comment in Neuron 39: 885-8; F1000 reviewed]
Erskine L, Williams SE, Brose K, Kidd T, Rachel RA, Goodman CS, Tessier-Lavigne M, and Mason CA (2000). Retinal ganglion cell axon guidance in the mouse optic chiasm: expression and function of Robos and Slits. J Neurosci 20: 4975-82. PMID: 10864955
List of publications from PubMed