Lats1 and Lats2 regulate YAP and TAZ activity to control the development of mouse Sertoli cells.

Recent reports suggest that the Hippo signaling pathway regulates testis development, though its exact roles in Sertoli cell differentiation remain unknown. Here, we examined the functions of the main Hippo pathway kinases, large tumor suppressor homolog kinases 1 and 2 (Lats1 and Lats2) in developing mouse Sertoli cells. Conditional inactivation of Lats1/2 in Sertoli cells resulted in the disorganization and overgrowth of the testis cords, the induction of a testicular inflammatory response and germ cell apoptosis. Stimulated by retinoic acid 8 (STRA8) expression in germ cells additionally suggested that germ cells may have been preparing to enter meiosis prior to their loss. Gene expression analyses of the developing testes of conditional knockout animals further suggested impaired Sertoli cell differentiation, epithelial-to-mesenchymal transition, and the induction of a specific set of genes associated with Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ)-mediated integrin signaling. Finally, the involvement of YAP/TAZ in Sertoli cell differentiation was confirmed by concomitantly inactivating Yap/Taz in Lats1/2 conditional knockout model, which resulted in a partial rescue of the testicular phenotypic changes. Taken together, these results identify Hippo signaling as a crucial pathway for Sertoli cell development and provide novel insight into Sertoli cell fate maintenance.

Abou Nader N ，Charrier L ，Meisnsohn MC ，Banville L ，Deffrennes B ，St-Jean G ，Boerboom D ，Zamberlam G ，Brind'Amour J ，Pépin D ，Boyer A ... -  《-》

Lats1 and Lats2 are required for ovarian granulosa cell fate maintenance.

Tsoi M ，Morin M ，Rico C ，Johnson RL ，Paquet M ，Gévry N ，Boerboom D ... -  《-》

Hippo pathway-mediated YAP1/TAZ inhibition is essential for proper pancreatic endocrine specification and differentiation.

Wu Y ，Qin K ，Xu Y ，Rajhans S ，Vo T ，Lopez KM ，Liu J ，Nipper MH ，Deng J ，Yin X ，Ramjit LR ，Ye Z ，Luan Y ，Arda HE ，Wang P ... -  《eLife》

Targeted Disruption of Lats1 and Lats2 in Mice Impairs Testis Development and Alters Somatic Cell Fate.

Abou Nader N ，Ménard A ，Levasseur A ，St-Jean G ，Boerboom D ，Zamberlam G ，Boyer A ... -  《INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES》

Hippo-YAP/TAZ signalling coordinates adipose plasticity and energy balance by uncoupling leptin expression from fat mass.

Adipose tissues serve as an energy reservoir and endocrine organ, yet the mechanisms that coordinate these functions remain elusive. Here, we show that the transcriptional coregulators, YAP and TAZ, uncouple fat mass from leptin levels and regulate adipocyte plasticity to maintain metabolic homeostasis. Activating YAP/TAZ signalling in adipocytes by deletion of the upstream regulators Lats1 and Lats2 results in a profound reduction in fat mass by converting mature adipocytes into delipidated progenitor-like cells, but does not cause lipodystrophy-related metabolic dysfunction, due to a paradoxical increase in circulating leptin levels. Mechanistically, we demonstrate that YAP/TAZ-TEAD signalling upregulates leptin expression by directly binding to an upstream enhancer site of the leptin gene. We further show that YAP/TAZ activity is associated with, and functionally required for, leptin regulation during fasting and refeeding. These results suggest that adipocyte Hippo-YAP/TAZ signalling constitutes a nexus for coordinating adipose tissue lipid storage capacity and systemic energy balance through the regulation of adipocyte plasticity and leptin gene transcription.

Choi S ，Kang JG ，Tran YTH ，Jeong SH ，Park KY ，Shin H ，Kim YH ，Park M ，Nahmgoong H ，Seol T ，Jeon H ，Kim Y ，Park S ，Kim HJ ，Kim MS ，Li X ，Bou Sleiman M ，Lee E ，Choi J ，Eisenbarth D ，Lee SH ，Cho S ，Moore DD ，Auwerx J ，Kim IY ，Kim JB ，Park JE ，Lim DS ，Suh JM ... -  《-》