Kumar explores regulation of male germline stem cell niche
By Raluca Dumitru
In a talk Jan. 6 at NIEHS, Rajendra Kumar, Ph.D., presented new findings on the fundamental role that gonadotropin hormones play in male reproductive health, offering insights into the mechanisms responsible for infertility and hypogonadism, or insufficient production of the male sex hormone. With rates of infertility on the rise, Kumar’s research clearly addresses a significant public health concern.
Hosted by NIEHS lead researcher Humphrey Yao, Ph.D., Kumar’s talk was part of the Laboratory of Reproductive and Developmental Toxicology (LRDT) Seminar Series. “Dr. Kumar’s research identifies new molecular mechanisms underlying male germline differentiation,” Yao said. “Components of these mechanisms could be susceptible to genetic mutations and environmental insults, which could be the causes of idiopathic infertility in humans.”
Kumar is an associate professor in the Department of Molecular and Integrative Physiology at the University of Kansas Medical Center. His research is focused towards understanding the complex regulation of the hypothalamus-pituitary-gonadal (HPG) axis by using unique mouse models that reproduce human reproductive diseases. His work is clinically relevant and will enhance understanding of the basic biology of the niche environment. Long term, Kumar’s research may pave the way for optimizing conditions for germ cell transplantation studies.
As Kumar explained, the male germline stem cell niche is controlled by extrinsic, intrinsic, and epigenetic factors. Key events involved in fertility, such as the development and production of the male and female germ cells required to form a new individual, or gametogenesis; the synthesis of steroid hormones, or steroidogenesis; and testis development, are carefully regulated by the HPG axis. Alterations in this network can lead to abnormalities of reproductive tract development and may result in idiopathic infertility, as well as the occurrence of gonadotropin-dependent testicular cancers.
Homing in on follicle stimulating hormone
Haploid gametes arise from a tightly controlled differentiation process that begins with precursor cells, which undergo multiple rounds of differentiation and maturation. “The most important factor for a proper gametogenesis is the microenvironment or the niche that is essential for maintaining spermatogonia self-renewal capacity and subsequent differentiation,” Kumar told the audience. “Surprisingly, little is known about niche regulation or how the niche regulates the stem cells.”
In his talk, Kumar showed that follicle stimulating hormone (FSH), a hormone produced by the pituitary gland, regulates the proliferation and differentiation of Sertoli cells, a major component of the germline stem cell niche. “By controlling the somatic cells indirectly,” Kumar said, “gonadotropin hormones such as FSH maintain the microenvironment within the reproductive system.” In the absence of FSH from the testis, the mice displayed hypogonadism, but were still fertile. So the next question was why the loss of FSH causes such a mild phenotype.
Cyclin D2 is important for the maintenance of the germline stem cell niche integrity
Sertoli cell proliferation is regulated by the cyclin D kinases and, intriguingly, the loss of cyclin D2 in a mouse model creates a phenotype similar to the one resulting from the loss of FSH. To investigate whether there are interactions between the FSH and cyclin D signaling pathways, Kumar’s team performed gene arrays followed by computational network analysis. The results showed a minimal overlap between these two pathways. Using knock-out and knock-in mouse models, Kumar demonstrated next that removing cyclin D2 in the FSH knock-out background exacerbates the phenotype and the mice displayed hypogonadism, as well as infertility.
Proper gametogenesis depends on an intact germline stem cell niche
Near the end of his talk, Kumar described the mechanism underlying such a severe phenotype. He showed that the integrity of the membrane of the niche is compromised in the double mutant, with the loss of FSH and cyclin D2. Subsequently, this loss of membrane integrity causes a failure of the germ cells to adhere to Sertoli cells, leading to sperm ultrastructure abnormalities and infertility.
These promising results raise new questions, such as understanding what upstream factor regulates cyclin D2.
(Raluca Dumitru, M.D., Ph.D., is an Intramural Research Training Award (IRTA) fellow in the NIEHS Laboratory of Molecular Carcinogenesis Stem Cell Biology Group.)