The relationship between small RNAs and male infertility

Work done in the lab of Dr. Subeer S. Majumdar at National Institute of Immunology, New Delhi, India.

About author

Dr. Alka has a bachelor’s in Microbiology (St. Xavier’s College, Kolkata) and a master’s in Biochemistry from the University of Calcutta. During her Master’s she did a dissertation at SINP, Kolkata, India where she had her first experience of lab research. This encouraged her to pursue further research and she joined the National Institute of Immunology, New Delhi for her Ph.D. under the supervision of Dr. Subeer Majumdar, to study small RNAs in male infertility. Currently, Alka is working as a Postdoctoral researcher with Dr. Upasna Sharma at the University of California Santa Cruz, USA. She has been awarded the IBSC-CIRM postdoctoral fellowship for her work on paternal epigenetic inheritance via small RNAs. Besides science, she enjoys talking to new people to hear their stories. She is also an amazing cook and hopes to run an Indian food chain someday, at least in Santa Cruz where she is currently residing.

Interview

How would you explain your research outcomes to the non-scientific community?

There is an increasing trend in the global cases of infertility, especially in urban populations. 50% of infertility cases are due to the malefactor and 33% of such incidents are due to unknown reasons – known as idiopathic male infertility. My work involves studying the cause and finding the mechanism of such cases. Our lab looks at the genetic and beyond (epigenetic) aspects of this topic, where my work revolves around understanding how small RNAs can regulate the functioning and maturation of a particular cell type – the Sertoli cells (Sc) – which are closely associated with sperm production.

We know that hormones regulate various bodily functions and the reproductive system is no exception. One critical hormone involved in male reproduction is FSH or Follicle Stimulating Hormone, which controls the growth and differentiation of Sc. The exciting phenomenon about these cells is that they behave differently during the initial growth phase (infancy) than in later phases beyond puberty. I found some small RNAs (microRNAs) to be high during infancy and low in pubertal Sc. Focusing on one specific microRNA called miR-92a-3p, we found that FSH reduces the expression of this small RNA in pubertal Sc. Since miR-92a-3p levels go down in puberty, we artificially overexpressed this microRNA in cultured cells and generated a transgenic mouse that had high levels of this microRNA at puberty, thereby defying the natural downregulation of its levels in Sc. Interestingly, high levels of miR-92a-3p in pubertal Sc damaged the cells and made them incapable of producing sperm. Changes in microRNA levels in testis could thus be an underlying cause of failed sperm production and infertility.

How do these findings contribute to your research area?

The reasons behind 33% of male infertility cases are unknown and my work provides a possible explanation. This work sheds light on how a single small RNA can induce a cascade of events to ultimately culminate in complete infertility. Our data can be helpful to diagnose cases of idiopathic infertility using miR- 92a-3p as a potential marker of fertility and such individuals can be cured by manipulating the expression of miR-92a-3p in the testis using transient transfections with viral vectors or in cultures using testicular biopsies. Such findings generate avenues to study what causes small RNA expression levels to change and how they can be regulated as a potential point of treatment for patients with infertility.

“Findings generate avenues to study what causes small RNA expression levels to change and how they can be regulated as a potential point of treatment for patients with infertility.”

What was the exciting moment during your research?

Though this work has been exciting throughout, I was ecstatic to see phenotypical results in transgenic mice. These mice had very small testis and almost no sperm in an otherwise completely healthy body.

What do you hope to do next?

I am currently exploring this field further with an approach to understand what is inherited from the father apart from the genetic information. I study changes in sperm small RNA with fathers’ diet, environmental exposure, etc., and how this information is passed to the next generation.

Where do you seek scientific inspiration from?

Once I knew I wanted to work on epigenetic and small RNAs, I started discussing them in various biological aspects and was intrigued to learn the endless regulation of cellular functions by these tiny RNA fragments. I seek inspiration from other people’s work and often have thorough discussions with my peers.

How do you intend to help Indian science improve?

Indian science is definitely on the upward growth trend, though there are still scopes of improvement. I would like to bring more talks about collaboration to the table and give PhD scholars access to learning other important skills that can help them explore all options in science and research. One major correction in Indian science would include regular stipends and better policies for amalgamating academia and industries through courses, internships, workshops, etc.

Reference

Gupta A, Vats A, Ghosal A, Mandal K, Sarkar R, Bhattacharya I, Das S, Pal R, Majumdar SS. Follicle-stimulating hormone-mediated decline in miR-92a-3p expression in pubertal mice Sertoli cells is crucial for germ cell differentiation and fertility. Cell Mol Life Sci. 2022 Feb 18;79(3):136. doi: 10.1007/s00018-022-04174-9. PMID: 35181820.

Copy Editor

Ritvi Shah

Postgraduate at Vikram Sarabhai Institute

Postgraduate at Vikram Sarabhai Institute of Cell and Molecular Biology, Gujarat. She is a neuroscience enthusiast. Apart from that, she enjoys reading and trying her hand at sciart.

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