Amotl2a interacts with the Hippo effector Yap1 and the Wnt/β-catenin effector Lef1 to control tissue size in zebrafish

Abstract

During development, proliferation must be tightly controlled for organs to reach their appropriate size. While the Hippo signaling pathway plays a major role in organ growth control, how it senses and responds to increased cell density is still unclear. In this study, we use the zebrafish lateral line primordium (LLP), a group of migrating epithelial cells that form sensory organs, to understand how tissue growth is controlled during organ formation. Loss of the cell junction-associated Motin protein Amotl2a leads to overproliferation and bigger LLP, affecting the final pattern of sensory organs. Amotl2a function in the LLP is mediated together by the Hippo pathway effector Yap1 and the Wnt/β-catenin effector Lef1. Our results implicate for the first time the Hippo pathway in size regulation in the LL system. We further provide evidence that the Hippo/Motin interaction is essential to limit tissue size during development.DOI: http://dx.doi.org/10.7554/eLife.08201.001

Proliferation-independent regulation of organ size by Fgf/Notch signaling

“…The size of the migrating primordium is partially controlled by the Hippo pathway components amotl2a (a tight junction-associated scaffolding protein) and yap1 (a transcriptional co-activator) (Agarwala et al, 2015). amotl2a inhibits proliferation, whereas yap1 is required in the primordium to reach its normal size.…”

“…The only manipulation described that causes an increase in neuromast size is the upregulation of Wnt signaling, while the size of the primordium increases after inhibition of the Hippo pathway member amotl2a (Agarwala et al, 2015; Head et al, 2013; Wada et al, 2013; Wada and Kawakami, 2015; Jacques et al, 2014). The Hippo pathway controls organ size via a kinase cascade that leads to the phosphorylation and degradation of the transcriptional co-activators Yap/Taz (Sun and Irvine, 2016).…”

“…In the absence of pathway activation, Yap/Taz are translocated to the nucleus where they activate proliferation and survival genes. The Wnt pathway affects organ size via controlling proliferation, which, at least partially, is regulated by amotl2a (Agarwala et al, 2015). In contrast, loss of the transcriptional co-activator yap1 rescues the amotl2a overproliferation phenotype but does not interact with the Wnt pathway.…”

Yap/Taz-TEAD ACTIVITY LINKS MECHANICAL CUES TO CELL PROGENITOR BEHAVIOR DURING HINDBRAIN SEGMENTATION

“…http://dx.doi.org/10.1101/366351 doi: bioRxiv preprint first posted online Jul. 10, 2018; expressed in the embryo (Agarwala et al, 2015), the Yap protein is enriched in hindbrain boundaries, and preferentially localized inside the nucleus when compared to rhombomeric cells ( Figure 1H-H'', see arrows in H'' pointing to boundary cells where Yap and DAPI colocalized). To determine whether Yap was acting as a cofactor of transcription for TEAD protein in these cells, we monitored the TEAD activity in vivo by using the transgenic reporter line Tg[4xGTIIC:d2GFP] that carries a promoter containing 4 multimerized GTIIC sequences, which are consensus TEAD-binding sites (Miesfeld & Link, 2014).…”

“…For morpholino knockdowns, embryos were injected at one-cell stage with splicingblocking morpholino oligomers (MOs) obtained from GeneTools, Inc. MOs were as follows: MO-p53 (Langheinrich et al, 2002), MO-Yap (Agarwala et al, 2015), MO-wwtr1 5'-CTG GAG AGG ATT ACC GCT CAT GGT C-3', MO-Rac3b (see MO-Rac3bSBI4E5 in (Letelier et al, 2018). For controls, random 25N morpholino was injected.…”