NHGRI logo

Genetic Disease Research Branch


Genomics, Development and Disease Section


B.S. University of Massachusetts, 1985

Ph.D. Johns Hopkins School of Medicine, 1991


Dr. William Pavan received his B.S. in animal science from the University of Massachusetts, Amherst and his Ph.D. in physiology from the Johns Hopkins School of Medicine, Baltimore. He completed his post-doctoral fellowship in the laboratory of Shirley Tilghman, Ph.D., at Princeton University in which he studied the developmental genetics of mouse coat color pigmentation.

Subsequently, Dr. Pavan joined NHGRI in 1994, when he began a research program focused on using genomic tools and genetic manipulation of model systems to decipher genome function and to dissect gene regulatory pathways in development and disease. His primary areas of interest include the development and diseases of melanocytes, the cells responsible for pigmentation of skin and hair, and the lysosomal storage disorder Niemann-Pick disease, Type C.

By integration of basic science research with clinical information from human patients, Dr. Pavan works to identify developmental pathways that regulate development, discover the alterations in these pathways that lead to disease, and develop paradigms for therapeutic interventions. Dr. Pavan's group first discovered the neural crest cell transcription factor SOX10, which is associated with Waardenburg Syndrome IV and with human melanoma, and also identified the lysosomal transmembrane protein, NPC1, whose mutation results in Niemann-Pick disease, type C1.

Scientific Summary

The Genomics, Development and Disease Section (GDDS; originally called the Mouse Embryology Section) was established in 1994 on the foundation that transformative and translational discoveries will be revealed through the application of advanced genetic and genomic approaches to the study of mouse genetic mutants that model human disease traits. The section uses a wide array of genomic tools along with the genetic manipulation of model systems to discover genome function and to dissect gene regulatory pathways in development and disease.

The main areas of research interest are the genetics of pigmentation and its diseases and the lysosomal storage disease Niemann-Pick disease, type C (NPC). With the ultimate goal of annotating human genome function with an emphasis on understanding and treating human diseases, Dr. Pavan's work is focused on transformative research that will provide insights into mammalian developmental pathways, disease pathology and therapeutic interventions.This approach has been highly successful. Dr. Pavan's section has discovered critical genetic components needed for normal development and/or postnatal homeostasis in 20 mouse mutant strains, with over half of these being instructive regarding orthologous human diseases. In 1998, Dr. Pavan's section discovered that mutations of the HMG-box transcription factor SOX10 result in neural crest stem cell defects in mice that accurately model enteric nervous system deficiencies offile://msgr_image/?msgr_image#2051524096 Hirschsprung (HSCR) disease and melanocyte deficiencies of Waardenburg (WS) syndrome. Subsequently, germline SOX10 mutations were identified in individuals with WS-HSCR disease. Next, the GDDS worked with the NHGRI genomics and embryology core facilities to develop technologies to further examine the transcriptional target genes of SOX10 in stem cell biology and explore SOX10's relationship to other HSCR and WS disease genes.

In 1997, Dr. Pavan's group used a mouse mutant that modeled the neurodegenerative and associated cholesterol and glycolipid storage defects of NPC to discover the underlying molecular defect in the protein NPC1 that was responsible for the disease traits. They went on to use this information to reveal that the orthologous human gene NPC1 is also mutated in individuals with NPC. Further animal modeling studies demonstrated neuronal-targeted expression of NPC1 rescued neurodegenerative disease, essential information for designing therapeutic interventions.

More recently, the Pavan group has further explored these pathways in development and disease as well as developed genetic screens to identify additional disease pathway components. Routinely they have occupied the forefront of research innovation by using high-risk modifier screens to identify major modifiers of primary genetic defects. They have expanded understanding of SOX10's contribution to human disease by demonstrating that somatic mutations of the SOX10 melanocyte stem cell transcriptional regulatory pathway are present in human melanoma, the most lethal form of skin cancer in the United States that is increasing in incidence worldwide.

These findings led to the hypothesis that altering SOX10 levels in melanoma may alter melanomagenesis. To identify SOX10 modulatory factors, they used comparative genomic sequencing analyses and zebrafish transgenic technologies to reveal cis-acting genomic elements that regulate SOX10 expression. To identify SOX10 target genes, they built genomic resources to interrogate transcriptional regulatory pathways in development and melanoma, integrating ChIP-seq, in vivo modeling, computational analyses and machine learning to identify a predictive sequence vocabulary involved in melanocyte gene expression. To identify trans-acting components that synergize with SOX10 stem cell function and thus may be targets for intervention in melanoma procession, they established a SOX10-sensitized genetic screen.

From this screen, nine mutant loci were identified that targeted multiple biological pathways; examples included identification of a role for the exon junction complex in stem cell maintenance and DNA integrity, discovery that NRG1/ERBB3 pathway activation is required in order to retain stem cell fate and it is again re-activated during human melanoma progression, and analysis of RPS7 mutations that resulted in expansion of the repertoire of RPS-associated phenotypes of Diamond-Blackfan anemia to include CNS and morphological traits. The Pavan group's NPC work has continued in a multi-lab effort aimed at developing and assessing effective NPC treatment strategies. This has involved collaborations with the NIH's National Chemical Genomics Center to identify candidate therapeutic compounds via high-throughput screens, its Therapeutics for Rare and Neglected Diseases program to bridge the gaps between basic discoveries and clinical trials, and NIH Clinical Center physicians for identification of biomarkers and bioassays as well as evaluation of compounds in NPC disease patients. They have also collaborated in establishment of a natural history study to identify screening criteria and biomarkers for use in gauging therapeutic interventions.

Current studies in the GDDS focus on transformative research that will simultaneously reveal new details of development and disease pathways and also provide candidate pathways for evaluation in human therapeutic interventions. The group continues to further examine the links between melanocyte development and melanoma by identifying modifiers of SOX10 in adult melanocyte stem cells and melanoma, and by examining SOX10's role in genome regulation. These studies include identification of in vivo genetic modifiers of hair graying, a novel model for study of MCSC that will allow discovery of genetic pathways that impact adult MCSC and may have far-reaching impact towards understanding adult stem cells, regeneration medicine, and melanoma research, since pathways utilized to maintain MCSC may also be involved in stem cell properties of melanoma cells. They are analyzing chromatin modifications of target genes using ChIP-seq analyses in studies that utilize genetic manipulations, such as loss- and gain-of-function SOX10 alleles, and candidate pharmacological interventions. In addition, they are collaborating with an international consortium to assemble a cohort of HSCR disease patients who will be evaluated for microbiome changes associated with enterocolitis, which occurs at a rate of 30 percent in HSCR patients and is the major morbidity associated with this neurocristopathy. Identification of altered HSCR microbiome populations may provide a means of early prognosis and potential therapeutic management.

The group continues to identify compounds for treatment of NPC and assess these compounds in animal models with the goal of translating this information into clinical trials at the NIH. Collectively, these future studies are designed to utilize the most current genomic technologies in combination with mouse models to facilitate effective disease therapy


Loftus SK, Morris JA, Carstea ED, Gu JZ, Cummings C.,Brown A, Ellison J, Ohno K, Rosenfeld MA, Tagle DA, Pentchev PG, Pavan WJ. Murine model of Niemann-Pick C disease: Mutation in a cholesterol homeostasis gene. Science, 277(5323):232-235. 1997. [PubMed]

Carstea ED, Morris JA, Coleman KG, Loftus SK, Zhang D, Cummings C, Gu J, Rosenfeld MA, Pavan WJ, Krizman DB, Nagle J, Polymeropoulos MH, Sturley SL, Ioannou YA, Higgins ME, Comly M, Cooney A, Brown A, Kaneski CR, Blanchette-Mackie EJ, Dwyer NK, Neufeld EB, Chang TY, Liscum L, Strauss JF, Ohno K, Zeilger M, Carmi R, Solkol J, Markie D, O'Neil RR, Van Diggelen OP, Elleder M, Patterson MC, Brady RO, Vanier MT, Pentchev PG, Tagle DA. The Neimann-Pick C gene: Homology to mediators of cholesterol homeostasis. Science, 277:228-231. 1997. [PubMed]

Southard-Smith EM, Kos L, Pavan WJ. Sox10 mutation disrupts neural crest development in Dom Hirschsprung mouse model. Nat Genet, 18:60-64. 1998. [PubMed]

Southard-Smith M., Angrist M., Ellison J., Agarwala R., Baxevanis A., Chakravarti A., Pavan W.J. The Sox10(Dom) mouse: modeling the genetic variation of Waardenburg-Shah (WS4) syndrome. Genome Res, 9(3): 215-225. 1999. [PubMed]

Loftus SK, Larson, DM, Baxter LL, Antonellis A, Chen Y, Wu X, Bittner M , Hammer JA, Pavan WJ. Mutation of Melanosome Protein RAB38 in chocolate Mice. Proc Natl Acad Sci U S A, 99(7): 4471-4476. 2002. [PubMed]

Pollock PM, Cohen-Solal K, Sood R, Namkoong J, Koganti A, Zhu H, Robbins C, Makalowska I, Martino JJ, Shin S-S, Marin Y, Roberts KG, Yudt LM, Chen A, Cheng J, Incao A, Pinkett HW, Graham CL, Dunn K, Crespo-Carbone SM, Mackason KR, Ryan KB, Sinsimer D, Goydos J, Reuhl KR, Eckhaus M, Meltzer PS, Pavan WJ, Trent JM, Chen S. Melanoma mouse model implicates metabotropic glutamate signaling in melanocytic neoplasia. Nature Genet, 34(1):108-12. 2003. [PubMed]

Hou L, Arnheiter H, Pavan WJ. Interspecies difference in the regulation of melanocyte development by SOX10 and MITF. Proc Natl Acad Sci U S A, 103(24):9081-5. 2006. [PubMed]

Silver DL, Hou L, Somerville R, Young ME, Apte SS, Pavan WJ. The secreted metalloprotease ADAMTS20 is required for melanoblast survival. PLoS Genet, 29;4(2):e1000003. 2008. [PubMed]

Watkins-Chow DE, Pavan WJ. Genomic copy number and expression variation within the C57BL/6J inbred mouse strain. Genome Res, (1):60-6. 2008. [PubMed]

Antonellis A, Huynh JL, Lee-Lin SQ, Vinton RM, Renaud G, Loftus SK, Elliot G, Wolfsberg TG, Green ED, McCallion AS, Pavan WJ. Identification of neural crest and glial enhancers at the mouse Sox10 locus through transgenesis in zebrafish. PLoS Genet, 4:e1000174. 2008. [PubMed]

Buac K, Watkins-Chow DE, Loftus SK, Larson DM, Incao A, Gibney G, Pavan WJ. A Sox10 expression screen identifies an amino acid essential for Erbb3 function. PLoS Genet, 4:e1000177. 2008. [PubMed]

Silver DL, Watkins-Chow DE, Schreck KC, Pierfelice TJ, Larson DM, Burnetti AJ, Liaw HJ, Myung K, Walsh CA, Gaiano N, Pavan WJ. The exon junction complex component Magoh controls brain size by regulating neural stem cell division. Nature Neurosci, 13:551-558. 2010. [PubMed]

Gorkin DU, D Lee, X Reed, C Fletez-Brant, SL Bessling, SK Loftus, MA Beer, Pavan WJ and AS McCallion. Integration of ChIP-seq and Machine Learning Reveals Enhancers and a Predictive Regulatory Sequence Vocabulary in Melanocytes. Genome Res, 22(11):2290-301. 2012. [PubMed]

Xu M, Liu K, Swaroop M, Porter FD, Sidhu R, Firnkes S, Ory DS, Marugan JJ, Xiao J, Southall N, Pavan WJ, Davidson C, Walkley SU, Remaley AT, Baxa U, Sun W, McKew JC, Austin CP, Zheng W. ?-Tocopherol reduces lipid accumulation in Niemann-Pick type C1 and Wolman cholesterol storage disorders. J Biol Chem, 287(47):39349-60. 2012. [PubMed]

Watkins-Chow DE, Cooke J, Pidsley R, Edwards A, Slotkin R, Leeds KE, Mullen R, Baxter LL, Campbell TG, Salzer MC, Biondini L, Gibney G, Phan Dinh Tuy F, Chelly J, Morris HD, Riegler J, Lythgoe MF, Arkell RM, Loreni F, Flint J, Pavan WJ, Keays DA. Mutation of the diamond-blackfan anemia gene Rps7 in mouse results in morphological and neuroanatomical phenotypes. PLoS Genet, 9(1):e1003094. doi: 10.1371/journal.pgen.1003094. 2013. [PubMed]

Harris ML, Buac K, Shakhova O, Hakami RM, Wegner M, Sommer L, Pavan WJ. A dual role for SOX10 in the maintenance of postnatal melanocyte lineage and the differentiation of melanocyte stem cell progenitors. PLoS Genet, 9(7):e1003644. 2013. [PubMed]

Rodriguez-Gil JL, Larson DM, Wassif CA, Yanjanin NM, Anderson SM, Kirby MR, Trivedi NS, Porter FD, Pavan WJ. A somatic cell defect is associated with the onset of neurological symptoms in a lysosomal storage disease. Mol Genet Metab, 110(1-2):188-90. 2013. [PubMed]

Fu R, Wassif CA, Yanjanin NM, Watkins-Chow DE, Baxter LL, Incao A, Liscum L, Sidhu R, Firnkes S, Graham M, Ory DS, Porter FD, Pavan WJ. Efficacy of N-acetylcysteine in phenotypic suppression of mouse models of Niemann-Pick disease, type C1. Hum Mol Genet, 22(17):3508-23. 2013. [PubMed]

Cronin JC, Watkins-Chow DE, Incao A, Hasskamp JH, Schönewolf N, Aoude LG, Hayward NK, Bastian BC, Dummer R, Loftus SK, Pavan WJ. SOX10 ablation arrests cell cycle, induces senescence, and suppresses melanomagenesis. Cancer Res, 73(18):5709-18. 2013. [PubMed]

Praetorius C, Grill C, Stacey SN, Metcalf AM, Gorkin DU, Robinson KC, Van Otterloo E, Kim RS, Bergsteinsdottir K, Ogmundsdottir MH, Magnusdottir E, Mishra PJ, Davis SR, Guo T, Zaidi MR, Helgason AS, Sigurdsson MI, Meltzer PS, Merlino G,Petit V, Larue L, Loftus SK, Adams DR, Sobhiafshar U, Emre NC, Pavan WJ, Cornell R, Smith AG, McCallion AS, Fisher DE, Stefansson K, Sturm RA, Steingrimsson E. A polymorphism in IRF4 affects human pigmentation through a tyrosinase-dependent MITF/TFAP2A pathway. Cell, 155(5):1022-33. 2013. [PubMed]

Fufa TD, Harris ML, Watkins-Chow DE, Levy D, Gorkin DU, Gildea DE, Song L, Safi A, Crawford GE, Sviderskaya EV, Bennett DC, Mccallion AS, Loftus SK, Pavan WJ. Genomic analysis reveals distinct mechanisms and functional classes of SOX10-regulated genes in melanocytes. Hum Mol Genet., 24(19):5433-50. 2015. [PubMed]

Genomics, Development and Disease Section Staff

Stacie Loftus, Ph.D.
Stacie Loftus, Ph.D.
  • Associate Investigator
  • Genomics, Development and Disease Section
Generic Profile Photo
Dawn Watkins-Chow, Ph.D.
  • Biologist
  • Genomics, Development and Disease Section
Denise Larson
Denise Larson, B.A.
  • Biologist
  • Genomics, Development and Disease Section
Laura Baxter
Laura Baxter
  • Biologist
  • Genomics, Development and Disease Section
Arturo A. Incao
Arturo A. Incao
  • Biologist
  • Genomics, Development and Disease Section

Last updated: March 15, 2018