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
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Copyright Dalle Nogare and
Chitnis. This article is distributed under
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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)