DPLM Faculty Profiles — Dr. Scott Williams

Scott Williams, PhD

Scott E. Williams, PhD

Assistant Professor

Office: 919-966-2737

E-mail: scott_williams@med.unc.edu

C.V. (PDF)

Research Interests

The mammalian skin epithelium 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. 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, 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.

 

Williams figure 1

 

Selected Publications

Williams SE, Beronja S, Pasolli HA and Fuchs E (2011). Asymmetric cell divisions promote Notch-dependent epidermal differentiation. Nature 470: 353-358. [Pubmed]

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. [Pubmed]

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 [Pubmed]

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. [Pubmed]

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. [Pubmed]

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. [Pubmed]

Williams SE, Mason CA, and Herrera E (2004). The optic chiasm as a midline choice point. Curr Opin Neurobiol 14: 51-60. [Pubmed]

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. [Pubmed]

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. [Pubmed]


View list of publications from
PubMed

PubMed Articles
Par3-mInsc and Gαi3 cooperate to promote oriented epidermal cell divisions through LGN.
Related Articles

Par3-mInsc and Gαi3 cooperate to promote oriented epidermal cell divisions through LGN.

Nat Cell Biol. 2014 Aug;16(8):758-69

Authors: Williams SE, Ratliff LA, Postiglione MP, Knoblich JA, Fuchs E

Abstract
Asymmetric cell divisions allow stem cells to balance proliferation and differentiation. During embryogenesis, murine epidermis expands rapidly from a single layer of unspecified basal layer progenitors to a stratified, differentiated epithelium. Morphogenesis involves perpendicular (asymmetric) divisions and the spindle orientation protein LGN, but little is known about how the apical localization of LGN is regulated. Here, we combine conventional genetics and lentiviral-mediated in vivo RNAi to explore the functions of the LGN-interacting proteins Par3, mInsc and Gαi3. Whereas loss of each gene alone leads to randomized division angles, combined loss of Gnai3 and mInsc causes a phenotype of mostly planar divisions, akin to loss of LGN. These findings lend experimental support for the hitherto untested model that Par3-mInsc and Gαi3 act cooperatively to polarize LGN and promote perpendicular divisions. Finally, we uncover a developmental switch between delamination-driven early stratification and spindle-orientation-dependent differentiation that occurs around E15, revealing a two-step mechanism underlying epidermal maturation.

PMID: 25016959 [PubMed - indexed for MEDLINE]

Oriented divisions, fate decisions.
Related Articles

Oriented divisions, fate decisions.

Curr Opin Cell Biol. 2013 Dec;25(6):749-58

Authors: Williams SE, Fuchs E

Abstract
During development, the establishment of proper tissue architecture depends upon the coordinated control of cell divisions not only in space and time, but also direction. Execution of an oriented cell division requires establishment of an axis of polarity and alignment of the mitotic spindle along this axis. Frequently, the cleavage plane also segregates fate determinants, either unequally or equally between daughter cells, the outcome of which is either an asymmetric or symmetric division, respectively. The last few years have witnessed tremendous growth in understanding both the extrinsic and intrinsic cues that position the mitotic spindle, the varied mechanisms in which the spindle orientation machinery is controlled in diverse organisms and organ systems, and the manner in which the division axis influences the signaling pathways that direct cell fate choices.

PMID: 24021274 [PubMed - indexed for MEDLINE]

A role for the primary cilium in Notch signaling and epidermal differentiation during skin development.
Related Articles

A role for the primary cilium in Notch signaling and epidermal differentiation during skin development.

Cell. 2011 Jun 24;145(7):1129-41

Authors: Ezratty EJ, Stokes N, Chai S, Shah AS, Williams SE, Fuchs E

Abstract
Ciliogenesis precedes lineage-determining signaling in skin development. To understand why, we performed shRNA-mediated knockdown of seven intraflagellar transport proteins (IFTs) and conditional ablation of Ift-88 and Kif3a during embryogenesis. In both cultured keratinocytes and embryonic epidermis, all of these eliminated cilia, and many (not Kif3a) caused hyperproliferation. Surprisingly and independent of proliferation, ciliary mutants displayed defects in Notch signaling and commitment of progenitors to differentiate. Notch receptors and Notch-processing enzymes colocalized with cilia in wild-type epidermal cells. Moreover, differentiation defects in ciliary mutants were cell autonomous and rescued by activated Notch (NICD). By contrast, Shh signaling was neither operative nor required for epidermal ciliogenesis, Notch signaling, or differentiation. Rather, Shh signaling defects in ciliary mutants occurred later, arresting hair follicle morphogenesis in the skin. These findings unveil temporally and spatially distinct functions for primary cilia at the nexus of signaling, proliferation, and differentiation.

PMID: 21703454 [PubMed - indexed for MEDLINE]

Developmental roles for Srf, cortical cytoskeleton and cell shape in epidermal spindle orientation.
Related Articles

Developmental roles for Srf, cortical cytoskeleton and cell shape in epidermal spindle orientation.

Nat Cell Biol. 2011 Mar;13(3):203-14

Authors: Luxenburg C, Pasolli HA, Williams SE, Fuchs E

Abstract
During development, a polarized epidermal sheet undergoes stratification and differentiation to produce the skin barrier. Through mechanisms that are poorly understood, the process involves actin dynamics, spindle reorientation and Notch signalling. To elucidate how epidermal embryogenesis is governed, we conditionally targeted serum response factor (Srf), a transcription factor that is essential for epidermal differentiation. Unexpectedly, previously ascribed causative defects are not responsible for profoundly perturbed embryonic epidermis. Seeking the mechanism for this, we identified actins and their regulators that were downregulated after ablation. Without Srf, cells exhibit a diminished cortical network and in mitosis, they fail to round up, features we recapitulate with low-dose actin inhibitors in vivo and shRNA-knockdown in vitro. Altered concomitantly are phosphorylated ERM and cortical myosin-IIA, shown in vitro to establish a rigid cortical actomyosin network and elicit critical shape changes. We provide a link between these features and Srf loss, and we show that the process is physiologically relevant in skin, as reflected by defects in spindle orientation, asymmetric cell divisions, stratification and differentiation.

PMID: 21336301 [PubMed - indexed for MEDLINE]

Asymmetric cell divisions promote Notch-dependent epidermal differentiation.
Related Articles

Asymmetric cell divisions promote Notch-dependent epidermal differentiation.

Nature. 2011 Feb 17;470(7334):353-8

Authors: Williams SE, Beronja S, Pasolli HA, Fuchs E

Abstract
Stem and progenitor cells use asymmetric cell divisions to balance proliferation and differentiation. Evidence from invertebrates shows that this process is regulated by proteins asymmetrically distributed at the cell cortex during mitosis: Par3-Par6-aPKC, which confer polarity, and Gα(i)-LGN/AGS3-NuMA-dynein/dynactin, which govern spindle positioning. Here we focus on developing mouse skin, where progenitor cells execute a switch from symmetric to predominantly asymmetric divisions concomitant with stratification. Using in vivo skin-specific lentiviral RNA interference, we investigate spindle orientation regulation and provide direct evidence that LGN (also called Gpsm2), NuMA and dynactin (Dctn1) are involved. In compromising asymmetric cell divisions, we uncover profound defects in stratification, differentiation and barrier formation, and implicate Notch signalling as an important effector. Our study demonstrates the efficacy of applying RNA interference in vivo to mammalian systems, and the ease of uncovering complex genetic interactions, here to gain insights into how changes in spindle orientation are coupled to establishing proper tissue architecture during skin development.

PMID: 21331036 [PubMed - indexed for MEDLINE]

Rapid functional dissection of genetic networks via tissue-specific transduction and RNAi in mouse embryos.
Related Articles

Rapid functional dissection of genetic networks via tissue-specific transduction and RNAi in mouse embryos.

Nat Med. 2010 Jul;16(7):821-7

Authors: Beronja S, Livshits G, Williams S, Fuchs E

Abstract
Using ultrasound-guided in utero infections of fluorescently traceable lentiviruses carrying RNAi or Cre recombinase into mouse embryos, we have demonstrated noninvasive, highly efficient selective transduction of surface epithelium, in which progenitors stably incorporate and propagate the desired genetic alterations. We achieved epidermal-specific infection using small generic promoters of existing lentiviral short hairpin RNA libraries, thus enabling rapid assessment of gene function as well as complex genetic interactions in skin morphogenesis and disease in vivo. We adapted this technology to devise a new quantitative method for ascertaining whether a gene confers a growth advantage or disadvantage in skin tumorigenesis. Using alpha1-catenin as a model, we uncover new insights into its role as a widely expressed tumor suppressor and reveal physiological interactions between Ctnna1 and the Hras1-Mapk3 and Trp53 gene pathways in regulating skin cell proliferation and apoptosis. Our study illustrates the strategy and its broad applicability for investigations of tissue morphogenesis, lineage specification and cancers.

PMID: 20526348 [PubMed - indexed for MEDLINE]

Loss of p120 catenin and links to mitotic alterations, inflammation, and skin cancer.
Related Articles

Loss of p120 catenin and links to mitotic alterations, inflammation, and skin cancer.

Proc Natl Acad Sci U S A. 2008 Oct 7;105(40):15399-404

Authors: Perez-Moreno M, Song W, Pasolli HA, Williams SE, Fuchs E

Abstract
Tumor formation involves epigenetic modifications and microenvironmental changes as well as cumulative genetic alterations encompassing somatic mutations, loss of heterozygosity, and aneuploidy. Here, we show that conditional targeting of p120 catenin in mice leads to progressive development of skin neoplasias associated with intrinsic NF-kappaB activation. We find that, similarly, squamous cell carcinomas in humans display altered p120 and activated NF-kappaB. We show that epidermal hyperproliferation arising from p120 loss can be abrogated by IkappaB kinase 2 inhibitors. Although this underscores the importance of this pathway, the role of NF-kappaB in hyperproliferation appears rooted in its impact on epidermal microenvironment because as p120-null keratinocytes display a growth-arrested phenotype in culture. We trace this to a mitotic defect, resulting in unstable, binucleated cells in vitro and in vivo. We show that the abnormal mitoses can be ameliorated by inhibiting RhoA, the activity of which is abnormally high. Conversely, we can elicit such mitotic defects in control keratinocytes by elevating RhoA activity. The ability of p120 deficiency to elicit mitotic alterations and chronic inflammatory responses, that together may facilitate the development of genetic instability in vivo, provides insights into why it figures so prominently in skin cancer progression.

PMID: 18809907 [PubMed - indexed for MEDLINE]

A role for Nr-CAM in the patterning of binocular visual pathways.
Related Articles

A role for Nr-CAM in the patterning of binocular visual pathways.

Neuron. 2006 May 18;50(4):535-47

Authors: Williams SE, Grumet M, Colman DR, Henkemeyer M, Mason CA, Sakurai T

Abstract
Retinal ganglion cell (RGC) axons diverge within the optic chiasm to project to opposite sides of the brain. In mouse, contralateral RGCs are distributed throughout the retina, whereas ipsilateral RGCs are restricted to the ventrotemporal crescent (VTC). While repulsive guidance mechanisms play a major role in the formation of the ipsilateral projection, little is known about the contribution of growth-promoting interactions to the formation of binocular visual projections. Here, we show that the cell adhesion molecule Nr-CAM is expressed by RGCs that project contralaterally and is critical for the guidance of late-born RGCs within the VTC. Blocking Nr-CAM function causes an increase in the size of the ipsilateral projection and reduces neurite outgrowth on chiasm cells in an age- and region-specific manner. Finally, we demonstrate that EphB1/ephrin-B2-mediated repulsion and Nr-CAM-mediated attraction comprise distinct molecular programs that each contributes to the proper formation of binocular visual pathways.

PMID: 16701205 [PubMed - indexed for MEDLINE]

Temporal regulation of EphA4 in astroglia during murine retinal and optic nerve development.
Related Articles

Temporal regulation of EphA4 in astroglia during murine retinal and optic nerve development.

Mol Cell Neurosci. 2006 May-Jun;32(1-2):49-66

Authors: Petros TJ, Williams SE, Mason CA

Abstract
Eph receptors and their ephrin ligands play important roles in many aspects of visual system development. In this study, we characterized the spatial and temporal expression pattern of EphA4 in astrocyte precursor cell (APC) and astrocyte populations in the murine retina and optic nerve. EphA4 is expressed by immotile optic disc astrocyte precursor cells (ODAPS), but EphA4 is downregulated as these cells migrate into the retina. Surprisingly, mature astrocytes in the adult retina re-express EphA4. Within the optic nerve, EphA4 is expressed in specialized astrocytes that form a meshwork at the optic nerve head (ONH). Our in vitro and in vivo data indicate that EphA4 is dispensable for retinal ganglion cell (RGC) axon growth and projections through the chiasm. While optic stalk structure, APC proliferation and migration, retinal vascularization, and oligodendrocyte migration appear normal in EphA4 mutants, the expression of EphA4 in APCs and in the astrocyte meshwork at the ONH has implications for optic nerve pathologies.

PMID: 16574431 [PubMed - indexed for MEDLINE]

Foxd1 is required for proper formation of the optic chiasm.
Related Articles

Foxd1 is required for proper formation of the optic chiasm.

Development. 2004 Nov;131(22):5727-39

Authors: Herrera E, Marcus R, Li S, Williams SE, Erskine L, Lai E, Mason C

Abstract
In animals with binocular vision, retinal ganglion cell (RGC) axons from each eye sort in the developing ventral diencephalon to project to ipsi- or contralateral targets, thereby forming the optic chiasm. Ipsilaterally projecting axons arise from the ventrotemporal (VT) retina and contralaterally projecting axons primarily from the other retinal quadrants. The winged helix transcription factor Foxd1 (previously known as BF-2, Brain Factor 2) is expressed in VT retina, as well as in the ventral diencephalon during the formation of the optic chiasm. We report here that in embryos lacking Foxd1, both retinal development and chiasm morphogenesis are disrupted. In the Foxd1 deficient retina, proteins designating the ipsilateral projection, such as Zic2 and EphB1, are missing, and the domain of Foxg1 (BF-1) expands from nasal retina into the VT crescent. In retina-chiasm co-cultures, VT RGCs from Foxd1 deficient retina are not repulsed by chiasm cells, and in vivo many VT RGCs aberrantly project contralaterally. However, even though the ipsilateral program is lost in the retina, a larger than normal uncrossed component develops in Foxd1 deficient embryos. Chiasm defects include axon stalling in the chiasm and a reduction in the total number of RGCs projecting to the optic tract. In addition, in the Foxd1 deficient ventral diencephalon, Foxg1 invades the Foxd1 domain, Zic2 and Islet1 expression are minimized, and Slit2 prematurely expands, changes that could contribute to axon projection errors. Thus, Foxd1 plays a dual role in the establishment of the binocular visual pathways: first, in specification of the VT retina, acting upstream of proteins directing the ipsilateral pathway; and second, in the patterning of the developing ventral diencephalon where the optic chiasm forms.

PMID: 15509772 [PubMed - indexed for MEDLINE]

Mena and vasodilator-stimulated phosphoprotein are required for multiple actin-dependent processes that shape the vertebrate nervous system.
Related Articles

Mena and vasodilator-stimulated phosphoprotein are required for multiple actin-dependent processes that shape the vertebrate nervous system.

J Neurosci. 2004 Sep 15;24(37):8029-38

Authors: Menzies AS, Aszodi A, Williams SE, Pfeifer A, Wehman AM, Goh KL, Mason CA, Fassler R, Gertler FB

Abstract
Ena/vasodilator-stimulated phosphoprotein (VASP) proteins regulate the geometry of the actin cytoskeleton, thereby influencing cell morphology and motility. Analysis of invertebrate mutants implicates Ena/VASP function in several actin-dependent processes such as axon and dendritic guidance, cell migration, and dorsal closure. In vertebrates, genetic analysis of Ena/VASP function is hindered by the broad and overlapping expression of the three highly related family members Mena (Mammalian enabled), VASP, and EVL (Ena-VASP like). Mice deficient in either Mena or VASP exhibit subtle defects in forebrain commissure formation and platelet aggregation, respectively. In this study, we investigated the consequence of deleting both Mena and VASP. Mena-/-VASP-/- double mutants die perinatally and display defects in neurulation, craniofacial structures, and the formation of several fiber tracts in the CNS and peripheral nervous system.

PMID: 15371503 [PubMed - indexed for MEDLINE]

The optic chiasm as a midline choice point.
Related Articles

The optic chiasm as a midline choice point.

Curr Opin Neurobiol. 2004 Feb;14(1):51-60

Authors: Williams SE, Mason CA, Herrera E

Abstract
The mouse optic chiasm is a model for axon guidance at the midline and for analyzing how binocular vision is patterned. Recent work has identified several molecular players that influence the binary decision that retinal ganglion cells make at the optic chiasm, to either cross or avoid the midline. An ephrin-B localized to the midline, together with an EphB receptor and a zinc-finger transcription factor expressed exclusively in the ventrotemporal retina where ipsilaterally projecting retinal ganglion cells are located, comprise a molecular program for the uncrossed pathway. In addition, the mechanisms for axon divergence in the optic chiasm are discussed in the context of other popular models for midline axon guidance.

PMID: 15018938 [PubMed - indexed for MEDLINE]

Ephrin-B2 and EphB1 mediate retinal axon divergence at the optic chiasm.
Related Articles

Ephrin-B2 and EphB1 mediate retinal axon divergence at the optic chiasm.

Neuron. 2003 Sep 11;39(6):919-35

Authors: Williams SE, Mann F, Erskine L, Sakurai T, Wei S, Rossi DJ, Gale NW, Holt CE, Mason CA, Henkemeyer M

Abstract
In animals with binocular vision, retinal ganglion cell (RGC) axons either cross or avoid the midline at the optic chiasm. Here, we show that ephrin-Bs in the chiasm region direct the divergence of retinal axons through the selective repulsion of a subset of RGCs that express EphB1. Ephrin-B2 is expressed at the mouse chiasm midline as the ipsilateral projection is generated and is selectively inhibitory to axons from ventrotemporal (VT) retina, where ipsilaterally projecting RGCs reside. Moreover, blocking ephrin-B2 function in vitro rescues the inhibitory effect of chiasm cells and eliminates the ipsilateral projection in the semiintact mouse visual system. A receptor for ephrin-B2, EphB1, is found exclusively in regions of retina that give rise to the ipsilateral projection. EphB1 null mice exhibit a dramatically reduced ipsilateral projection, suggesting that this receptor contributes to the formation of the ipsilateral retinal projection, most likely through its repulsive interaction with ephrin-B2.

PMID: 12971893 [PubMed - indexed for MEDLINE]

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