Humphrey Hung-Chang Yao, Ph.D.
Reproductive & Developmental Biology Laboratory / Reproductive Developmental Biology Group
Building 101, Room C458A
111 T.W. Alexander Drive
Research Triangle Park, NC 27709
Compelling animal evidence and human epidemiological data have revealed that impairment of fetal organ development has profound consequences on adult health. This concept of "fetal origins of adult diseases" also applies to the reproductive systems where formation of most reproductive organs is completed before birth. Defects in reproductive organ formation manifest as birth defects in severe cases (i.e. pseudohermaphroditism). However, minor abnormalities are often left undetected and become a potential cause of fertility problems and neoplasia when the affected individual reaches adulthood. Our Group is using organogenesis of the gonads and reproductive tracts as the model to understand the basic process of organ formation as well as the potential implication on impacts of endocrine disruptor exposure on reproductive system development in fetuses and fertility in adulthood. Reproductive organs are one of the few organs that exhibit dramatic sex-specific pattern of dimorphic development. This unique pattern of development provides a model system to understand not only the mechanism of sexual differentiation, but also how progenitor cells make decision to differentiate into tissue-specific cell types, the fundamental concept of embryology. Synapses of two major projects are provided below:
- Identify the sources of somatic cell lineages in the fetal gonads and investigate how they acquire their organ-specific identities
Organs are composed of common cell types, such as fibroblasts and vasculature endothelial cells, and specialized cell types that define the unique functions of the organs. These specialized cells are thought to originate from organ-specific progenitor cells and acquire their identity during embryogenesis. Using mouse gonads as a model organ we study how progenitor cells make decision to differentiate into various tissue-specific cell types. Testis and ovary derive from a common primordium during embryogenesis. The primordium, through cell automatous fate determination and intercellular signaling, gives rise to cell types unique to testis (Sertoli, Leydig, and peritubular myoid cells) and ovary (granulosa, theca, and unknown somatic stem cells). Using genetic lineage tracing mouse models, we first characterize the progenitor cells in the primordium and study their sex specification process. In the fetal ovary, we discover the lineage transition of granulosa cells from progenitor state (Steroidogenic factor 1 or SF1 positive) to initial fate specification (FOXL2 positive). This lineage transition process is actively suppressed in the fetal testis by the TGFβ pathway, therefore allowing the progenitor cells to differentiate into FOXL2-negative Sertoli cells.
- Define the cellular and molecular processes that lead to sexually dimorphic establishment of the reproductive tracts
Before sexual differentiation occurs, embryos are anatomically bisexual as they possess both male and female reproductive tracts. These two tracts derive from two separate progenitor systems in the fetal mesonephros: Wolffian duct for the male tract and Müllerian duct for the female tract. In the male embryos, Wolffian ducts are maintained by testis-derived androgens while Müllerian duct undergo regression induced by anti-Müllerian hormone, also a product of testes. Female embryos, which do not produce androgens or anti-Müllerian hormone (AMH), experience the opposite where Müllerian ducts are maintained and Wolffian ducts undergo regression. In search of novel regulators in this process, we discovered the presence of orphan nuclear receptor COUPTFII in the mesenchyme of the mesonephros. Inactivation of COUPTFII specifically in the mesonephric mesenchyme leads to maintenance of both Wolffian and Müllerian ducts in the male and female mouse embryos, a typical case of pseudohermaphroditism. The affected embryos still have sex-specific production of hormones (androgen and AMH), indicating that hormonal abnormality is not responsible for the pseudohermaphroditic phenotypes of the reproductive tracts. Instead, COUPTFII in the mesenchyme of the mesonephros appears to be a molecular switch that controls the decision-making process of the identity of reproductive tract progenitors.
Dr. Humphrey Hung-Chang Yao leads the Developmental Reproductive Biology Group in the Laboratory of Reproductive and Developmental Toxicology at NIEHS/NIH at Research Triangle Park in North Carolina. Dr. Yao received his doctoral degree at the University of Illinois in Urbana-Champaign in 1999 and then completed his postdoctoral training at Duke University Medical Center in 2002. He became Assistant Professor in the Department of Comparative Biosciences at University of Illinois in Urbana-Champaign in 2003 and received tenure in 2009. Dr. Yao is the recipient of the Basal O'Connor Starter Research Award from March of Dimes Birth Defect Foundation, Pfizer Research Award, New Investigator Award for the Society for the Study of Reproduction, and Young Andrologist Award from the American Society of Andrology. Dr. Yao joined NIEHS/NIH as a tenure-track investigator on August 9, 2010.
Rodriguez KF, Ungewitter EK, Crespo-Mejias Y, Liu C, Nicol B, Kissling GE, Yao HH. Effects of in Utero Exposure to Arsenic during the Second Half of Gestation on Reproductive End Points and Metabolic Parameters in Female CD-1 Mice. Environ Health Perspect. 2016;124(3):336-43.
Tomaszewski J, Joseph A, Archambeault D, Yao HH. Essential roles of inhibin beta A in mouse epididymal coiling. Proc Natl Acad Sci U S A. 2007;104(27):11322-7.
Barsoum IB, Kaur J, Ge RS, Cooke PS, Yao HH. Dynamic changes in fetal Leydig cell populations influence adult Leydig cell populations in mice. FASEB J. 2013;27(7):2657-66.
Liu C, Peng J, Matzuk MM, Yao HH. Lineage specification of ovarian theca cells requires multicellular interactions via oocyte and granulosa cells. Nat Commun. 2015;6:6934.
Archambeault DR, Yao HH. Activin A, a product of fetal Leydig cells, is a unique paracrine regulator of Sertoli cell proliferation and fetal testis cord expansion. Proc Natl Acad Sci U S A. 2010;107(23):10526-31.