Research Interests
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 鈥渟imple鈥� 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,听in utero听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.
Selected Publications
Williams SE听and Lough KJ. Cell biology: Pardon the听intrusion.听Curr Biol听2020 Dec 21; 30(24): R1481-4. doi: 10.1016/j.cub.2020.10.036.听
Lough听KJ, Spitzer DC, Bergman AJ, Wu JJ, Byrd KM,听奥颈濒濒颈补尘蝉听厂贰. Cleft palate听is caused by disruption of the nectin-afadin cell-cell adhesion complex.听Development听2020听Jul 13; 147(21):dev.189241. 听[Special issue听on 鈥淭he Origins and Mechanisms of Developmental Disorders鈥漖.听
Lough听KJ, Byrd KM, Descovich CP, Spitzer DC, Bergman AJ, Beaudoin III GM, Reichardt听LF and听Williams SE. Telophase correction refines division orientation听in听stratified epithelia.听eLife听2019 Dec 13;8. pii: e49249.听
Byrd听KM, Piehl NC, Patel JH, Huh WJ, Sequeira I, Lough KJ, Wagner BL, Marangoni P,听Watt FM, Klein OD, Coffey RJ,听Williams SE. Heterogeneity within听stratified听epithelial stem cell populations maintains the oral mucosa in response to听physiological stress.听Cell Stem Cell听2019 Dec 5; 25(6): 814-29.听
Carper MB,听Troutman S, Wagner BL, Byrd KM, Selitsky SR, Parag-Sharma K, Henry EC, Li W,听Parker JS, Montgomery SA, Cleveland JL,听Williams SE, Kissil JL,听Hayes DN,听Amelio AL. An immunocompetent mouse model of HPV16(+) head and neck squamous听cell carcinoma.听Cell Reports听2019 Nov 5;29(6):1660-1674.e7.听
Lough KJ, Byrd KM, Spitzer DC, and听Williams SE听(2017). Closing the gap: mouse models to study adhesion in secondary palatogenesis.听J Dent Res听[Special Issue on Orofacial Clefting, Craniofacial and Dental Anomalies] Available online August 17, 2017.听
Byrd KM, Lough KJ, Patel JH, Descovich CP, Curtis TA and听Williams SE听(2016). LGN plays distinct roles in oral epithelial stratification, filiform papilla morphogenesis and hair follicle development.听Development听143(15): 2803-17.听听[Selected for Cover, F1000 reviewed]
Williams SE*, Garcia I, Crowther AJ, Stewart A, Li S, Stewart A, Liu H, Lough, KJ, O鈥橬eill S, Veleta K, Oyarzabal EA, Merrill JR, Shi YI and Gershon TR* (2015). Aspm sustains postnatal cerebellar neurogenesis and medulloblastoma growth in mice.听Development听142(22): 3921-32.听听*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.听Nat Cell Biol听16(8): 758-69.听听[F1000 reviewed]
Williams SE听and Fuchs E (2013). Oriented divisions, fate decisions.听Curr Opin Cell Biol听25(6):749鈥�758.听
Williams SE, Beronja S, Pasolli HA and Fuchs E (2011). Asymmetric cell divisions promote Notch-dependent epidermal differentiation.听Nature听470: 353-358.听听[Comment in听Nat Rev Genetics听12: 226; F1000 reviewed].
Ezratty E, Stokes N, Chai S, Shah A,听Williams SE听and Fuchs E (2011). A role for the primary cilium in Notch signaling and epidermal differentiation during skin development.听Cell听45: 1129-41.听
Luxenburg C, Pasolli HA,听Williams SE听and Fuchs E (2011). Developmental roles for Srf, cortical cytoskeleton and cell shape in epidermal spindle orientation.听Nat Cell Biol听13: 203-14.听听[F1000 reviewed]
Beronja S, Livshits G,听Williams SE听and Fuchs E (2010). Rapid functional dissection of genetic networks via tissue-specific transduction and RNAi in mouse embryos.听Nat Med听16: 821-7.听
Perez-Moreno M, Song W, Pasolli HA,听Williams SE听and Fuchs E (2008). Loss of p120 catenin and links to mitotic alterations, inflammation and skin cancer.听PNAS听105: 15399-404.听听[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.听Neuron听50: 535-47.听听[Comment in听Neuron听50: 519-21]
Williams SE, Mason CA, and Herrera E (2004). The optic chiasm as a midline choice point.听Curr Opin Neurobiol听14: 51-60.听
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.听Neuron听39: 919-935.听听[Comment in听Neuron听39: 885-8; F1000 reviewed]
Erskine L,听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.听J Neurosci听20: 4975-82.听
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