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    • The Hippo pathway is a growth control signaling

    2022-05-27

    The Hippo pathway is a growth control signaling cascade that has been demonstrated to play an important role in regulating cell proliferation and differentiation [5,6]. The core signaling pathway consists of a group of kinases which negatively regulate the expression of transcriptional co-activators YAP/TAZ. Inactivation of the Hippo pathway is a characteristic feature of daunorubicin undergoing rapid proliferation whereas active Hippo signaling is known to be associated with cellular differentiation [8]. Change in the activity of Hippo signaling has been previously reported to regulate the balance between cell proliferation and differentiation in a number of different cell types [10,22,23]. However, there is limited information on the role of this pathway in the mammalian testes. We have previously reported that transcriptional co-activator YAP is an important regulator of cyclic-AMP signaling and CREB phosphorylation in pubertal (19-day) rat Sc [14]. In the present study, we investigated if the Hippo signaling pathway components are differentially expressed in the infant (highly proliferative) and pubertal (functionally mature, non proliferative) Sc. To this end, Sc were isolated and cultured from 5-day (infant) and 19-day (pubertal) rats and the basal expression of the core Hippo pathways components was analyzed. We found that the expression of the Hippo kinases- Stk3 and Stk4 was significantly up-regulated in pubertal Sc as compared to infant Sc. Similarly, the expression of Large tumor suppressor Kinase 1 (Lats1) was significantly elevated in pubertal cells as compared to infant Sc. In contrast, Lats2 expression did not shown any significant change in the two age groups. High expression of the Hippo and Lats kinases in pubertal cells correlated well with the cessation of Sertoli cell proliferation that is observed at the onset of puberty. Intriguingly, assessment of Yap expression revealed significantly higher expression of Yap in pubertal Sc as compared to infant Sc. The expression of transcriptional co-activator Taz did not show any significant change between the two age groups. The increase in Yap mRNA was reflected at the protein level as well, with stronger YAP immunostaining being observed in the nuclei and cytoplasm of 19-day Sc as compared to 5-day Sc. The increase in YAP expression at the onset of puberty is interesting as it indicated the probable role of other factors besides the core Hippo and Lats Kinases in regulating YAP expression and sub-cellular localization. It has been previously reported that FSH mediated c-AMP signaling is compromised in infant Sc, which limits the expression of genes involved in germ cell division and differentiation during infancy [16,21,24]. In contrast, FSH augments c-AMP synthesis in pubertal Sc to induce the expression of c-AMP responsive genes such as Kitlg, Gdnf et cetera which are important for spermatogenesis [16,25,26]. Yap has been previously reported to be regulated by c-AMP signaling [27]. The promoter of Yap gene has c-AMP response elements (CRE) which is bound by CREB to induce transcription of Yap mRNA [27]. Therefore, we determined whether FSH had differential effect on Yap mRNA expression in infant and pubertal Sc. Consistent with the differential actions of FSH in the two age groups, it was observed that FSH could induce a small but significant increase in Yap mRNA in pubertal Sc but not infant Sc. This suggested that high c-AMP might be responsible for elevated Yap expression observed in pubertal cells. Interestingly, c-AMP- PKA pathway has also been reported to negatively regulate YAP in some cell types [28,29]. PKA mediated activation of Lats kinase results in inhibition of YAP activity due to phosphorylation and subsequent degradation [[28], [29], [30]]. Therefore, we checked if FSH mediated c-AMP signaling regulated YAP phosphorylation in pubertal Sc. A significant increase in phosphorylated form of YAP was observed in 19-day Sc treated with FSH as compared to vehicle treated control Sc. The phosphorylation of YAP is associated with its sequestration in the cytoplasm and subsequent degradation [6,31]. However, we did not find any significant difference in the sub-cellular localization of YAP in FSH treated 19-day Sc. It is possible that the level of phosphorylation induced by FSH is not strong enough to cause an observable decline in the nuclear expression of YAP in these cells. It is also possible that other factors besides phosphorylation are involved in regulating YAP sub-cellular localization in Sc; this hypothesis, however, requires further investigation. Our results indicate a dual role of FSH in regulating YAP expression and activity in pubertal Sc. On one hand, FSH up-regulated Yap mRNA but at the same time keeps a check on YAP protein activity by inducing its phosphorylation.