Dissertation
THE ROLE OF RETINOIC ACID RECEPTOR ALPHA IN THE MALE GERM CELLS: GERM CELL-SPECIFIC MUTATIONAL PHENOTYPES AND RELATED TRANSCRIPTOME CHANGES OF THE BIOLOGICAL PROCESSES
Doctor of Philosophy (PhD), Washington State University
01/2019
Handle:
https://hdl.handle.net/2376/118441
Abstract
The active vitamin A, retinoic acid (RA), is essential for spermatogenesis in the testis, and as such, vitamin A-deficient (VAD) animals are infertile. Retinoic acid receptors (RARs) and retinoid X receptors (RXRs), each with alpha, beta, and gamma subtypes, are responsible for mediating RA signaling. Of these receptors, RAR alpha (RARA) has been demonstrated to be essential for spermatogenesis, as Rara-null mice experienced infertility.
To gain insight into the germ cell-specific role of RARA, we generated a germ cell-specific Rara knockout model (Rara cKO) and investigated the testicular phenotypes from neonatal ages through adulthood. In Rara cKO neonates, the undifferentiated spermatogonial number increased at postnatal day 2 (P2), suggesting the function of RARA in gonocytes. As expected, the RARA participated in spermatogonial differentiation, as demonstrated by reduced number of differentiated spermatogonia in the Rara cKO mice compared with the wild-type (WT) mice. In juvenile and adult Rara cKO mice, testes showed increased germ cell apoptosis, disrupted blood-testis-barrier (BTB), and severely disrupted germ cell organization, suggesting that RARA is needed for normal cell adhesions and germ cell organization. Additionally, meiotic progression was delayed, and the synaptonemal complexes were defective in the Rara cKO meiotic cells compared with the WT counterparts.
Comparative transcriptome analysis of RNAs isolated from enriched germ cells of the Rara cKO and WT mice at P4 and P8 uncovered genes for biological processes that could explain the aforementioned phenotypes. The genes with altered expression at P4 indicated that RARA regulates proliferation and differentiation of spermatogonia and spermatogonial stem cell (SSC) fate, and adhesion and migration, which can explain the altered numbers of undifferentiated spermatogonia seen in Rara cKO neonates, as well as the diminished capacity of Rara-mutated SSCs to reinitiate spermatogenesis. At P8, RARA is likely the principal regulator of the meiotic processes and cell adhesion and migration, which aligns with the synaptonemal complex defects and faulty BTB observed in the testis of Rara cKO mice. Collectively, these results support strongly that germ cell-specific RARA exerts broad functions throughout spermatogenesis, and is the ubiquitous regulator of proliferation, differentiation, adhesion, and meiotic processes in male germ cells.
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Details
- Title
- THE ROLE OF RETINOIC ACID RECEPTOR ALPHA IN THE MALE GERM CELLS: GERM CELL-SPECIFIC MUTATIONAL PHENOTYPES AND RELATED TRANSCRIPTOME CHANGES OF THE BIOLOGICAL PROCESSES
- Creators
- Natalie Rose Peer
- Contributors
- Kwanhee Kim (Advisor)
- Awarding Institution
- Washington State University
- Academic Unit
- School of Molecular Biosciences
- Theses and Dissertations
- Doctor of Philosophy (PhD), Washington State University
- Number of pages
- 201
- Identifiers
- 99900581415801842
- Language
- English
- Resource Type
- Dissertation