Connecting physical cues and tissue patterning

eLife, Oct 2015

Several signaling pathways work together, via a protein called Amotl2a, to establish the size and shape of a zebrafish sense organ primordium.

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Connecting physical cues and tissue patterning

Connecting physical cues and tissue patterning 0 S, K o ̈nig S , Eimer S , Ronneberger O 1 Duquesne S, Liu K , Boehm A, Grimm L, Link Several signaling pathways work together, via a protein called Amotl2a, to establish the size and shape of a zebrafish sense organ primordium. DAMIAN DALLE NOGARE AND AJAY B CHITNIS Image When zebrafish lack a protein called Amotl2a (bottom), the posterior Lateral Line Primordium increases in size and cell number Hippo effector Yap1 and Wnt/ß-catenin - Copyright Dalle Nogare and Chitnis. This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited. Htermine the global properties of an organ, ow do local interactions collectively delike its size and shape, in a developing embryo? Cells can alter how they grow and divide in response to a number of cues, including the mechanical tension between cells and how tightly packed the cells are, via a system called the Hippo signaling pathway (Shroeder and Halder, 2012). Now, in eLife, Virginie Lecaudey and colleagues at the Albert Ludwigs University of Freiburg – including Sobhika Agarwala as first author – have examined how a protein called Amotl2a links the Hippo pathway to other signaling pathways as the zebrafish posterior Lateral Line Primordium develops (Agarwala et al., 2015; Figure 1). This Primordium is the forerunner of a system of sense organs called the posterior Lateral Line that detects the flow of water over the zebrafish (Chitnis et al., 2012). The posterior Lateral Line Primordium starts as a group of about 125 cells that migrate collectively (under the skin) from the ear of the developing zebrafish to the tip of its tail. While the leading cells are relatively mesenchymal, the trailing cells organize into clusters (or “rosettes”) called proneuromasts. These are deposited at regular intervals as the Primordium moves towards the tail. The five or six proneuromasts deposited by the Primordium will develop into the neuromasts that act as the sensory organs of the posterior lateral line. Cells that are not incorporated into proneuromasts are deposited between neuromasts as so-called interneuromast cells. The Primordium shrinks as it moves, and resolves into two or three terminal neuromasts when it finally reaches the tail. The Wnt and FGF signaling systems coordinate the development of the posterior Lateral Line Primordium. FGF signaling promotes the formation of proneuromasts. In the leading cells, the activity of a Wnt signaling molecule called ß-catenin drives the expression of FGFs (Fibroblast Growth Factors) that activate FGF signaling by binding to their receptor proteins (Figure 1). However, this ß-catenin activity simultaneously inhibits the FGF receptors in the leading cells. As a result, only the trailing cells, where Wnt signaling is weaker, respond to FGF signaling and so form proneuromasts. FGF signaling also drives the expression of a diffusible antagonist molecule that blocks the receptors that are needed for Wnt signaling. This helps to restrict the area of active Wnt signaling to a progressively smaller leading zone. In turn, this allows more of the posterior Lateral Line Primordium to respond to FGF signaling, and so additional proneuromasts form closer to the leading edge. The transcriptional co-activators YAP and TAZ promote tissue growth and play a central role in Figure 1. Amotl2a expression limits growth in the posterior Lateral Line Primordium by inhibiting Yap1 and ß-catenin-dependent proliferation. Wnt signaling dominates in a leading zone (green), while FGF receptor activity dominates in a trailing zone (red). Wnt/ß-catenin signaling drives the expression of secreted FGF ligands; it also prevents a response to FGF in the leading cells by triggering the expression of Sef and Dusp6, inhibitors of FGF receptor activation. Activation of the FGF receptor in trailing cells causes proneuromasts to form. It also determines the expression of a diffusible antagonist of Wnt signaling, Dkk1b, which helps restrict Wnt/ß-catenin signaling to a progressively smaller leading zone. Both Wnt and FGF signaling promote cell proliferation in the posterior Lateral Line Primordium. FGF-dependent Amotl2a expression in the trailing zone inhibits proliferation determined by Yap1 and by ß-catenin. Black and red lines represent positive and negative regulatory interactions, respectively. Solid arrows represent intracellular regulatory interactions, while dashed lines represent interactions mediated by secreted factors. another signaling system called the Hippo path- Yap1. However, the hyperproliferation observed way (Varelas, 2014). Proteins called Motins in Amotl2a mutants is only partially rescued in provide a critical link between external cues, like mutant zebrafish that lack both Amotl2a and cell density, and the activity of YAP (Moleirinho Yap1, and remains higher than in mu (...truncated)


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Damian Dalle Nogare, Ajay B Chitnis. Connecting physical cues and tissue patterning, eLife, 2015, DOI: 10.7554/eLife.11375