During early embryonic development, and particularly during the initial steps of organogenesis, cell, tissues, and organs are separated by wide intracellular spaces filled by extracellular matrix (ECM). The extracellular matrix (ECM) plays pivotal roles in cell self-renewal, fate, death and signaling to regulate diverse function including migration, proliferation, and differentiation.
One of ECM components is hyaluronan (HA), a ubiquitously expressed glycosaminoglycan. HA can be detected in the organism in its high-molecular-weight (HMW) form. HMW-HA has been shown as a critical element during the phases of separation, migration, and colonization of the gonads by precursors of the gametes, the primordial germ cells (PGCs). Little is known about how HA regulates the number of PGCs, their differentiation, meiotic entry and establishment and maintenance of ovarian reserve. In the proposed research, we will test the overarching hypothesis that the stromal microenvironment of the fetal ovary, including an HA-rich matrix, regulates the establishment and maintenance of the ovarian reserve and reproductive longevity. To test this hypothesis, we will use the naked mole-rat (Heterocephalus glaber, NMR), mouse and human as a model.
To evaluate the role of vHMW-HA we will use transgenic mice that express the nmrHas2 in the different compartments/cells of mouse ovary using cell-specific Cre alleles. Evaluation of the conserved effect of high molecular hyaluronan in ovarian development we will evaluate the localization of HA in human ovaries, the total levels, and the gene expression. Taking this all together, this project will show the regulatory role of HA in the stromal microenvironment of the fetal ovary, and its functions in the establishment and maintenance of the ovarian.