Establishment of Sex-specific Reproductive Organs

Research Summary

Humphrey Yao, Ph.D., leads the Reproductive Developmental Biology Group in the Reproductive & Developmental Biology Laboratory (RDBL) at NIEHS. He also holds a secondary appointment in the NIEHS Epigenetics & Stem Cell Biology Laboratory. The main thrust of his group is to define the normal process of how embryos establish their sex-specific reproductive organs, and investigate whether this process is susceptible to in utero exposure to endocrine disruptors or maternal stress.

Compelling animal evidence and human epidemiological data have revealed that impairment of fetal organ development has profound consequences on adult health. The 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 disorders of sex development. However, minor abnormalities are often left undetected and become a potential cause of fertility problems and neoplasia when the affected individual reaches adulthood.

The Reproductive Developmental Biology Group uses organogenesis of the gonads, reproductive tracts, and external genitalia as a model to delineate the basic process of organ formation and the potential implication of the impacts of environment on reproductive organ formation 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 to understand not only the mechanism of sex determination, but also how progenitor cells make the decision to differentiate into tissue-specific cell types, the fundamental concept of embryology.

showing reproductive information on an embryo


Movie 1: Nr5a1;tdTomato+ cells undergo extensive and active migration during urethra closure.

Movie 2: EGFR/ERBB inhibitor (Lapatinib) prevents migration of Nr5a1;tdTomato+ cells ex vivo, leading to failure of urethra closure.

Major Areas of Research:

  • Understand how different somatic cell lineages (Sertoli and Leydig cells in the testis and granulose and theca cells in the ovary) are formed in the fetal testis and ovary, respectively.
  • Define the cellular processes that lead to sexually dimorphic establishment of the reproductive tracts and external genitalia.
  • Investigate the effects of in utero exposure to endocrine disruptors or maternal stress on organogenesis of reproductive organs and lingering impacts on fertility in adulthood.

Current Projects:

  • Define the linage progression roadmap of somatic cells in the gonads, reproductive tracts, and external genitalia by combined single cell mRNA and ATAC sequencing.
  • Identify novel players in gonadal organogenesis using conditional genetic approaches, ChIP-seq, ATAC-seq, and RNA-seq.
  • Uncover novel regulators (RUNX1, NR2F2, etc.) responsible for the establishment of dimorphic reproductive organs.
  • Examine the impact of in utero exposure to endocrine disrupting agents (arsenic and phthalates) and maternal heat stress on reproductive organ development and fertility.

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. Yao moved to NIEHS in 2010 and was promoted to Senior Investigator in 2018.