Abstract
The Hippo pathway is conserved and plays important roles in organ size control. The core components of the Hippo pathway are two kinases Hippo (Hpo), Warts (Wts), and a transcription-co-activator Yorkie (Yki). Yki activity is regulated by phosphorylation, which affects its nuclear localization and stability. To determine the role of the Hippo pathway in stem cells, we examine follicle stem cells (FSCs) in the Drosophila ovary. Yki is detected in the nucleus of FSCs. Knockdown of yki in the follicle cell lineage leads to a disruption of the follicular epithelium. Mitotic clones of FSCs mutant for hpo or wts are maintained in the niche and tend to replace the other FSCs, and FSCs mutant for yki are rapidly lost, demonstrating that the Hippo pathway is both required and sufficient for FSC maintenance. Using genetic interaction analyses, we demonstrate that the Hedgehog pathway acts upstream of the Hippo pathway in regulating FSC maintenance. The nuclear localization of Yki is enhanced when the Hedgehog signaling is activated. Furthermore, a constitutively active but not a wild-type Yki promotes FSC maintenance as activation of the Hedgehog signaling does, suggesting that the Hedgehog pathway regulates Yki through a post-translational mechanism in maintaining FSCs.
Highlights
Stem cells undergo self-renewal to produce daughter cells with identical properties of the mother cell and daughter cells that differentiate into different types of cells
We further examined the genetic interaction between the Hippo and Hedgehog pathway demonstrated previously by Kalderon’s laboratory22. ptc mutation leads to over-activation of the Hedgehog pathway and strongly promotes follicle stem cells (FSCs) maintenance[21]
We show that inhibition of Yki function results in loss of the FSC and disruption of the follicular epithelium
Summary
Stem cells undergo self-renewal to produce daughter cells with identical properties of the mother cell and daughter cells that differentiate into different types of cells. Main-body follicle cells undergo eight to nine rounds of cell divisions to maintain a mono-layered epithelium surrounding the egg chamber before they enter endocycle at stage 6 These follicle cells are important for yolk production and eggshell formation in the following steps of oogenesis[10, 11]. FSCs mutant for genes encoding for Drosophila Janus Kinase Hopscotch (Hop) or Stat Stat92E, are lost from the niche[17] Together, these data demonstrate that multiple signaling pathways contribute to FSC maintenance. A key component of the Hippo pathway Yorkie (Yki) has been suggested to regulate FSC maintenance downstream of the co-activator of Notch signaling Mastermind (Mam) and the Hedgehog pathway[22]. It is important to understand how the Hippo pathway integrates such complicated signaling networks to modulate cellular functions
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