HomeResearchIntramural ResearchResearch Branches at NHGRIGenetic Disease Research Branch Pavan Lab

William J. Pavan, Ph.D. Senior Investigator Genetic Disease Research Branch Head Mouse Embryology Section B.S. University of Massachusetts, 1985 Ph.D. Johns Hopkins School of Medicine, 1991 (301) 496-7584 (301) 402-2170 bpavan@nhgri.nih.gov Building 49, Room 4A82 49 Convent Dr, MSC 4472 Bethesda, MD 20892-4472 Selected Publications 2007 Pigment Cell Development Workshop Melanocyte Project 2004 Pigment Cell Development Workshop Greener Pastures: Exploring the Genetics of Pigmentation

Dr. Pavan's laboratory uses genomic tools to study how an embryo develops into a functioning organism. His group focuses on neural crest cells, a group of stem cells that differentiate into a wide variety of tissues throughout the body. Their research is relevant to a range of human developmental disorders.

In vertebrate development, neural crest cells form at the top of the neural tube, which later becomes the spinal cord. They then migrate throughout the body to populate the entire peripheral nervous system and form other tissues, such as craniofacial structures, part of the adrenal gland, and melanocytes-cells that, among other functions, determine skin, hair, and eye color. When the genetic machinery that controls neural crest cell development goes awry, it can cause many human diseases, ranging from Waardenburg syndrome to cleft lip and palate.

At least 15 genes have been shown to be important for the development of neural crest cells and their descendants, but hundreds of genes are probably involved. Dr. Pavan's laboratory uses animal models-most often mice-of neural crest cell disorder to identify the genes required for normal development. His laboratory is investigating how these genes function and whether the corresponding genes in humans are responsible for any human diseases. For example, many of the genes and mechanisms involved in normal melanocyte development also are involved in the progression of melanoma, a particularly aggressive type of skin cancer. Reactivation of the genetic pathways that enable neural crest-derived cells to migrate through the embryo may be responsible for melanoma's high metastasis rate.

Mice are particularly good models for studying melanocyte genetics because many strains with differing coat patterns have been preserved over the past two centuries, and each coat pattern reflects a different, spontaneous mutation in a gene or genes governing melanocyte development. Thus, no sophisticated assays are required to identify different phenotypes; researchers simply look at coat colors and patterns.

Dr. Pavan's team has identified a number of genes important to proper neural crest formation, including, for example, the gene for the transcription factor SOX10. Their studies found that SOX10 interacts with two other transcription factors, PAX3 and MITF. All three have human counterparts, and mutations in any of them can upset the normal differentiation of neural crest cells into melanocytes and other tissues. Dr. Pavan's laboratory also isolates and cultures undifferentiated mouse neural crest stem cells in vitro. This makes it possible both to study precisely how specific genetic mutations derail normal development and to insert genes in the cells in an effort to correct a mutation or to make the cells differentiate in specific directions. In addition to screening existing mouse strains, Dr. Pavan's laboratory runs a large-scale mutagenesis-screening program-generating new mutants and seeking to find additional genes that, when mutated, cause additional neural crest defects. These genes then become candidates for study as possible human disease genes.

Utilizing another set of genomic research tools, Dr. Pavan's laboratory has generated complementary DNA (cDNA) libraries representing expressed genes in several melanocyte-derived cells and cell lines. They use the cDNA data in microarray studies to find genes with similar expression patterns across different melanoma cell lines and then look for the same expression patterns in developing mouse embryos. This process has pointed the way to several previously unidentified genes that may be involved in human developmental diseases. His laboratory is now comparing genomic sequences from a wide variety of species - ranging from fish to birds to mammals - and looking for similarities in genes and in their regulatory regions.

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Last Updated: March 10, 2008