Titre de la thèse :

The involvement of Hippo Pathway in the physiology and pathophysiology of ovulation in cows

Mots-clés :

Hippo, cow, granulosa cells, theca cells, YAP, TEAD, VP, P17, cyst, COD.

Résumé :

The ovulatory process is initiated by a surge of LH that leads to the activation of the EGF receptor (EGFR) in granulosa cells (GC) which consequently stimulates the expression of several essential ovulatory genes. About 15% of infertility in cows is due to the presence of ovarian cysts that generally develop from pre-ovulatory follicles that fail to ovulate. In women and rodents, in addition to the essential physiological activity of Hippo signaling effectors for the EGF signaling in GC, their deregulation also plays an important role in anovulatory cystic disorders. To the best of our knowledge, no studies report physiological or pathophysiological roles of Hippo pathway effectors related to ovulation or ovarian cyst formation in cattle. The main objectives of the present thesis were, therefore, (1) to elucidate the importance of the physiological activity of Hippo signaling effectors in the pre-ovulatory cascade and anovulation in ruminants and (2) to determine whether dysregulation of YAP in bovine GC is implicated in the pathogenesis of the cystic ovarian disease (COD). The results are separated into two articles. In the first article, we employed a well-defined preovulatory GC culture system to show that YAP signaling is essential for expressing EGFR and the downstream target genes EREG, EGR1 and TNFAIP6. Most importantly, using an ultrasound-guided follicular injection system, we have also shown that the classic Hippo signaling inhibitor verteporfin inhibits GnRH-induced ovulation in vivo in cattle. In the second article, we employed a bovine model of spontaneous COD to show that YAP mRNA and protein abundance are significantly higher in granulosa and theca (TC) cells isolated from cystic follicles (follicular structures of at least 20 mm in diameter) compared to the respective cell types isolated from large non-cystic follicles (≥12 mm). Moreover, the phosphorylation pattern of YAP and the increased abundance of mRNA encoding classical YAP-TEAD target genes suggest that the transcriptional activity of YAP is increased in GC of follicular cysts compared to large non-cystic follicles. Together, these results show for the first time that the Hippo pathway is critical to the ovulatory cascade in cattle and its dysregulation may play a key role in the pathogenesis of cystic ovarian disease in this species.

Date / Heure : mercredi, 19 mars 2023 à 13:30

Local :  1134. 3200, rue Sicotte

Lien Zoom : https://umontreal.zoom.us/j/86826500347?pwd=QjRGVXJMN0dYM

ID de réunion : 868 2650 0347

Code secret : 920346

Jury :

• Bruce Murphy, Président
• Gustavo Zamberlam, Directeur de recherche
• Christopher Price, Codirecteur
• Imourana Alassane-Kpembi, Membre du jury
• Raj Duggavathi, Examinateur externe
• Kalidou Ndiaye, Représentant de la doyenne