Our Science – Hornyak Website

Thomas J. Hornyak, M.D., Ph.D.

Dermatology Branch Investigator Bldg. 10, Room 12-N-242 NCI, NIH, Bethesda MD 20892 Phone:   301-451-1926 Fax:   301-496-5370 E-Mail:   hornyakt@mail.nih.gov Link: Other Homepage

Biography

Dr. Hornyak obtained his A.B. in music from Princeton and his M.D. degree and Ph.D. degree in Biological Chemistry from The University of Michigan Medical School. His doctoral work in the laboratory of Dr. Jules A. Shafer at Michigan consisted of using enzyme and chemical kinetics to study the activation of blood coagulation factor XIII. He completed an internship in medicine at The New York Hospital - Cornell University Medical Center and a residency in dermatology at New York University (NYU) Medical Center. During a post-doctoral fellowship in the laboratory of Dr. Edward B. Ziff at NYU, he studied factors regulating dopachrome tautomerase/tyrosinase-related protein-2 expression and transcription factors regulating melanocyte development during embryogenesis.
In 1999, Dr. Hornyak joined the Department of Dermatology at the Henry Ford Health System as a staff member and independent investigator. He has received several NIH research grants and a New Investigator Award from the Department of Defense Neurofibromatosis Research Initiative. In 2003, Dr. Hornyak joined the Dermatology Branch, National Cancer Institute where he is a tenure-track investigator.

Research

Regulation of Melanocyte Development and Differentiation

Our lab is interested in melanocytes, the pigment-producing cells of the skin, hair follicle, eye, and ear. Much of our research activity stems from attempting to understand how melanocytes develop in the murine embryo. Melanocytes originate from neural crest cells during embryogenesis, and must undergo a complex migratory process, coupled with well-regulated proliferative expansion, to reach the skin and hair follicle in sufficient numbers to confer pigmentation to these organs. Expression of transcription factors from distinct structural classes, including Mitf, Pax3, and Sox10, is critical for melanocyte development to proceed properly, with mutations in any one of these factors resulting in pigmentation defects in both mice and humans.
We have shown that the transcription factors Mitf and Sox10 act synergistically to activate expression of Dct, encoding the accessory melanogenic enzyme dopachrome tautomerase/tyrosinase-related protein-2 (TRP 2), one of the melanogenic genes expressed early in melanocyte development soon after emigration from the neural crest. Transgenic mice expressing the lacZ gene from the Dct promoter have been useful for understanding the activities of Mitf, Pax3, and Sox10 on melanocyte development. Several different laboratories, using murine Mitf homozygous mutants and molecular and cellular techniques, have established the crucial role of Mitf in melanocyte survival and in mediating effects of extracellular signals. We observed that murine embryos with heterozygous mutations in Mitf have significantly fewer melanoblasts than wild-type embryos at early developmental stages, and that the time-dependent increase in cell number during development differs between heterozygous mutant and wild-type cells. There is evidence that human congenital disorders of pigmentation results from Mitf haploinsufficiency, suggesting that Mitf dosage in melanocytes may be critical for the regulation of melanocyte function. We are using murine Mitf mutants to explore the consequences of reductions of Mitf dosage In melanocytes on cell proliferation and survival. We are interested in how environment-dependent factors, such as differences between the environment of melanocytes in the inner ear and skin, can contribute to selective loss of melanocytes from those environments.
Melanocyte survival and production of melanin appears to be regulated not only by the intrinsic activities of transcription factors, but also by signaling pathways activated by extracellular factors such as endothelin-1, SCF/Kit ligand, and basic fibroblast growth factor (bFGF) acting via intracellular effectors such as the Ras proto-oncogene. The Ras-GTPase activating protein (RasGAP) neurofibromin is mutated in patients with type I neurofibromatosis (NF1) who have characteristic pigmentary lesions termed café-au-lait macules. We are using a murine model of human NF1, mice heterozygous for a knockout mutation in the gene Nf1, to understand the contribution of neurofibromin to normal pigmentary regulation both during melanocyte development and during melanocyte differentiation.

Signal Transduction, Melanocyte Transformation, and Melanoma Progression

Genomic and experimental studies have found somatic mutations in the genes BRAF and NRAS in malignant melanoma and benign and congenital melanocytic nevi, implying a role for the Ras proto-oncogene and its downstream effector B-Raf kinase in the control of melanocyte proliferation. A new interest of the lab is exploring in detail the role of Ras and its various effectors not only in the murine developmental systems described above, but also in the regulation of human melanocyte proliferation and melanocyte transformation.

This page was last updated on 6/11/2008.