Understanding reproductive aging regulation and mechanisms using a Caenorhabditis elegans model

Abstract

Human female reproductive capacity declines early in adulthood due to decreased oocyte quality, with higher rates of infertility, miscarriage, and birth defects especially after mid-30s. Recently, due to the work from our lab , the Kornfeld lab and the Ellis lab , <italic>C. elegans<italic> has emerged as a model to study reproductive aging. My thesis work focuses on (1) studying the genetic regulation of <italic>C. elegans<italic> reproductive cessation; (2) developing a systematic approach to analyze different steps involved in <italic>C. elegans<italic> reproductive aging; and (3) studying the underlying molecular mechanisms of reproductive aging.

Insulin/IGF-1 signaling (IIS) is known to regulate reproductive span in <italic>C. elegans<italic>. We found that TGF-ß Sma/Mab signaling is a novel reproductive span regulator that acts independently of known somatic aging regulators.

To discover the cause of <italic>C. elegans<italic> reproductive decline, we took a systematic approach and found that <italic>C. elegans<italic> reproductive span is also limited by oocyte quality, rather than ovulation rate, progeny number, or body size. Reduced TGF-ß Sma/Mab and IIS signaling delay reproductive aging through modulating multiple aspects of the reproductive process, including embryonic viability, oocyte fertilizability, chromosome segregation, DNA damage resistance, and morphology of the oocytes and germline. Furthermore, TGF-ß Sma/Mab and IIS pathways both act non-autonomously in the soma to regulate reproductive aging, and their activities are required at least partially in adulthood.

To find the mechanisms of how the two pathways regulate oocyte quality, we performed microarrays comparing wild-type with TGF-ß Sma/Mab or IIS mutant oocytes, and comparing young with old wild-type oocytes. We found that several molecular functions are critical for <italic>C. elegans<italic> oocyte quality maintenance, such as chromosome segregation, cell cycle, and DNA damage response. These transcriptional analyses revealed that the TGF-ß Sma/Mab regulation of reproductive aging is separable from its control of body size, and that IIS regulates reproductive and somatic aging through distinct mechanisms. Additionally, the gene effectors associated with oocyte quality are conserved between <italic>C. elegans<italic> and humans, suggesting that the molecular mechanisms underlying their oocyte quality control are similar. Therefore our study may also provide insights into understanding the fundamental mechanisms of oocyte quality maintenance in humans.