Le rôle de LATS1 et de LATS2 dans le développement du cortex surrénalien
The Hippo signaling pathway is a highly conserved kinase cascade that controls fundamental cellular processes such as proliferation, apoptosis and differentiation. In this cascade, the Large tumor suppressor kinase 1 and 2 (LATS1/2) phosphorylate and inactivate the main downstream effectors, Yes-associated protein (YAP) and Transcriptional coactivator with PDZ-binding motif (TAZ), to finely regulate the development, size and homeostasis of several organs. It was recently demonstrated that YAP and TAZ were essential for the maintenance of the adrenal cortex during adult life, but the role of the upstream kinases has never been studied. The objective of the present project was therefore to elucidate the role of LATS1 and LATS2 in adrenocortical development. We generated a Lats1flox/flox;Lats2flox/flox;Nr5a1-cre mouse model in which Lats1/2 were conditionally inactivated in steroidogenic cells. The characterization of this model revealed that Lats1/2 were required to maintain proper adrenocortical cell identity during embryonic development. In the absence of Lats1/2, adrenocortical cells acquire myofibroblastic properties and lose their steroidogenic capacity, leading to adrenal deficiency and death at 2 to 3 weeks of age. This transdifferentiation is probably caused, at least in part, by an increased transcriptional activity of YAP/TAZ since a stronger nuclear expression of YAP/YAZ and higher expression levels of Hippo target genes were observed in the myofibroblastic population. These results suggest an important novel role of Hippo signaling in adrenal cortex development.
LATS1 LATS2 YAP TAZ Hippo pathway Adrenal gland Adrenocortical cells Development Transgenic mice