The Hippo signaling pathway acts via the Yorkie (Yki)/Yes-associated protein (YAP) transcriptional coactivator family to control tissue growth in both Drosophila and mammals 1–3. Yki/YAP drives ...tissue growth by activating target gene transcription, but how it does so remains unclear. Here we identify Mask as a novel cofactor for Yki/YAP. We show that Drosophila Mask forms a complex with Yki and its binding partner, Scalloped (Sd), on target-gene promoters and is essential for Yki to drive transcription of target genes and tissue growth. Furthermore, the stability and subcellular localization of both Mask and Yki is coregulated in response to various stimuli. Finally, Mask proteins are functionally conserved between Drosophila and humans and are coexpressed with YAP in a wide variety of human stem/progenitor cells and tumors.
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► mask mutants generate yki-like phenotypes in Drosophila ► Mask and Yki are coregulated in response to various stimuli ► Mask forms a complex with Yki and Sd on promoter DNA ► Mask is required for Yki to drive transcription and growth
Wnt signalling induces a gradient of stem/progenitor cell proliferation along the crypt‐villus axis of the intestine, which becomes expanded during intestinal regeneration or tumour formation. The ...YAP transcriptional co‐activator is known to be required for intestinal regeneration, but its mode of regulation remains controversial. Here we show that the YAP‐TEAD transcription factor is a key downstream effector of Wnt signalling in the intestine. Loss of YAP activity by Yap/Taz conditional knockout results in sensitivity of crypt stem cells to apoptosis and reduced cell proliferation during regeneration. Gain of YAP activity by Lats1/2 conditional knockout is sufficient to drive a crypt hyperproliferation response. In particular, Wnt signalling acts transcriptionally to induce YAP and TEAD1/2/4 expression. YAP normally localises to the nucleus only in crypt base stem cells, but becomes nuclear in most intestinal epithelial cells during intestinal regeneration after irradiation, or during organoid growth, in a Src family kinase‐dependent manner. YAP‐driven crypt expansion during regeneration involves an elongation and flattening of the Wnt signalling gradient. Thus, Wnt and Src‐YAP signals cooperate to drive intestinal regeneration.
Synopsis
How the YAP‐TEAD transcriptional factor is regulated during intestinal repair and colorectal cancer remains debated. Here, genetic work identifies YAP and TEAD as transcriptional targets of Wnt signalling, with YAP nuclear localisation governed by Src family kinases, highlighting unexpected signal cooperation during murine tissue regeneration.
Depletion of Yap/Taz increases crypt stem cell apoptosis and reduces proliferation during regeneration in vivo.
Conditional activation of Yap/Taz by Lats1/2 depletion induces YAP nuclear localisation and crypt hyperplasia.
Genetic activation of Wnt signalling induces transcript expression of YAP and TEAD1/2/4 in intestinal organoids or tumours.
Irradiation‐induced nuclear localisation of YAP‐TEAD is regulated by Src family kinase, YAP‐TEAD activity and crypt regeneration are Wnt‐dependent.
Wnt transcriptionally controls YAP and TEAD expression to enable Src‐dependent activation of YAP‐TEAD activity during intestinal regeneration.
The study of P-element repression in Drosophila melanogaster led to the discovery of the telomeric Trans-Silencing Effect (TSE), a repression mechanism by which a transposon or a transgene inserted ...in subtelomeric heterochromatin (Telomeric Associated Sequence or TAS) has the capacity to repress in trans in the female germline, a homologous transposon, or transgene located in euchromatin. TSE shows variegation among egg chambers in ovaries when silencing is incomplete. Here, we report that TSE displays an epigenetic transmission through meiosis, which involves an extrachromosomal maternally transmitted factor. We show that this silencing is highly sensitive to mutations affecting both heterochromatin formation (Su(var)205 encoding Heterochromatin Protein 1 and Su(var)3-7) and the repeat-associated small interfering RNA (or rasiRNA) silencing pathway (aubergine, homeless, armitage, and piwi). In contrast, TSE is not sensitive to mutations affecting r2d2, which is involved in the small interfering RNA (or siRNA) silencing pathway, nor is it sensitive to a mutation in loquacious, which is involved in the micro RNA (or miRNA) silencing pathway. These results, taken together with the recent discovery of TAS homologous small RNAs associated to PIWI proteins, support the proposition that TSE involves a repeat-associated small interfering RNA pathway linked to heterochromatin formation, which was co-opted by the P element to establish repression of its own transposition after its recent invasion of the D. melanogaster genome. Therefore, the study of TSE provides insight into the genetic properties of a germline-specific small RNA silencing pathway.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Stem cells generate self-renewing and differentiating progeny over many rounds of asymmetric divisions. How stem cell growth rate and size are maintained over time remains unknown. We isolated ...mutations in a Drosophila melanogaster gene, wicked (wcd), which induce premature differentiation of germline stem cells (GSCs). Wcd is a member of the U3 snoRNP complex required for pre-ribosomal RNA maturation. This general function of Wcd contrasts with its specific requirement for GSC self-renewal. However, live imaging of GSCs within their niche revealed a pool of Wcd-forming particles that segregate asymmetrically into the GSCs on mitosis, independently of the Dpp signal sent by the niche. A fraction of Wcd also segregated asymmetrically in dividing larval neural stem cells (NSCs). In the absence of Wcd, NSCs became smaller and produced fewer neurons. Our results show that regulation of ribosome synthesis is a crucial parameter for stem cell maintenance and function.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
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