Hippo signaling in mammalian reproduction

Abstract

The Hippo signaling pathway, so named for its massive overgrowth mutant phenotypes, has become one of the most exciting signaling pathways to emerge in the field of reproductive biology. While disruption of Hippo is associated with tumorigenesis in many organs and tissues, relatively less is understood about the normal roles of Hippo signaling in the reproductive organs. Here, we highlight the recent literature illuminating the roles of Hippo pathway members in mouse and human reproduction. We place special emphasis on the inputs and outputs of Hippo signaling during preimplantation development, where Hippo signaling has been extensively studied in both mouse and human. We note a common emerging theme is the critical and highly conserved role of Hippo signaling in epithelia of the reproductive organs. We also discuss human reproductive disorders, whose etiology may be related to dysregulation of Hippo signaling, and possible therapies that have been proposed to correct this dysregulation. Finally, we describe the edge of our knowledge, which currently limits our understanding of Hippo signaling in reproductive health and disease.

Keywords: Hippo; decidualization; ovary; preimplantation; spermatogenesis; trophoblast reproductive disease.

Figure 1

Hippo signaling regulates cell fate specification in the mammalian early embryo. Starting around the 16-cell stage, angiomotin (AMOT) is localized to the symmetrically distributed adherens junctions, enabling activation of Hippo kinases LATS1/2. By contrast, trophectoderm (TE) cells are polarized along the radial axis, leading to AMOT tethering in the apical domain and rendering LATS1/2 inactive. In inside cells, active LATS1/2 phosphorylate transcriptional co-factors YAP1/WWTR1, which leads to their cytoplasmic retention and degradation. Meanwhile, in TE cells, YAP1/WWTR1 are free to enter the nucleus, where either partners with DNA binding protein TEAD4 to activate expression of Cdx2 and Gata3, and repress expression of Sox2.

Figure 2

Ovarian function requires dynamic Hippo signaling in somatic cells. (A) When Hippo signaling is experimentally repressed in granulosa cells, follicles suffer adverse effects such as loss and transdifferentiation of granulosa cells and oocyte death. (B) Requirements for Hippo signaling in granulosa cells change through the life of a follicle. In primordial follicles, Hippo signaling activity is high, restricting YAP1 to the cytoplasm and preventing premature follicle growth. At activation, Hippo signaling in granulosa cells decreases to allow YAP1 to enter the nucleus and induce follicle growth. As the follicle enters maturity before ovulation, nuclear YAP1 decreases again in granulosa cells, before spiking in preovulatory follicles and then dropping dramatically in response to the LH surge at ovulation. ‘Hippo kinase’ refers to LATS1/2 and MST1/2.

Figure 3

The dynamic changes of Hippo signaling components during TE expansion and establishment of chorionic villi. (A) In the trophectoderm (TE), YAP1 is nuclear, whereas it is cytoplasmic in the inner cell mass (ICM). During implantation, the polar TE makes contact with and invades the uterine epithelium. (B) The unique spatial distribution of Hippo pathway components in different trophoblast subtypes balances self-renewal and differentiation during trophoblast development. CTB, cytotrophoblast; STB, syncytiotrophoblasts; pCC, proximal cell column; dCC, distal cell column; EVT, extravillous trophoblast.

Figure 4

Testicular function requires Hippo signaling in somatic cells. When Hippo signaling is experimentally repressed in Sertoli cells, seminiferous tubules suffer adverse effects such as tissue fibrosis and germ cell death.