Science: Revealed that the Hippo signaling pathway directs abnormal organ growth, but not normal organ growth

Accurate growth control is essential
to ensure proper organ size and animal health.
Many signaling pathways regulate cell proliferation and apoptosis, which in turn determines organ size
.
However, mechanisms that can sense when developing organs reach proper size and indicate halting further growth remain elusive
.
These mechanisms may also coordinate regeneration and induce tumorigenesis
when defects occur.
In this context, the Hippo signaling pathway has attracted a lot of attention because experimental overactivation of its downstream effector --- transcriptional coactivator Yap/Taz/Yki--- can drive cell proliferation, leading to significant organ overgrowth and tumorigenesis
.

The Hippo signaling pathway integrates a variety of different biochemical and mechanical cell-cell and cell-extracellular matrix signals to regulate gene expression
through Yap/Taz/Yki.
In the current growth control model, the activity of Yap/Taz/Yki directs the proliferation of the right amount of cells during development, making them active when organs grow and inactivated
when growth is stopped.

In a new study, researchers from the Université de Leuven in Belgium and the Vrije Universiteit Brussels deduce that a signaling pathway that plays a key role in regulating organ growth should meet three requirements: (i) without its signal input, normal growth does not begin or end normally; (ii) its activity is related to the spatial and temporal patterns of cell proliferation; (iii) When overactivated, it produces larger but otherwise normal organs
.
Therefore, they investigated whether the Hippo signaling pathway meets these criteria
for organ growth control mechanisms.
The results of the study were published in the Nov.
18, 2022 issue of Science under the title "Hippo signaling instructs ectopic but not normal organ growth.
"

To address this hypothesis, the authors studied two commonly used models of organ growth control, the eye of fruit flies and the liver of mice, in which they investigated the effects of loss of output from the Hippo signaling pathway on growth, its activity patterns during normal development, and genetic programs
induced by experimental overactivation of Yap/Taz/Yki.

Functional analysis
of HIPPO signaling pathways in organ growth control.
Image from Science, 2022, doi:10.
1126/science.
abg3679
.

Their data showed that the output of the Hippo signaling pathway is not necessary
for the development and proliferation of liver precursor cells and Drosophila retinal cells.
In addition, the transcriptional activity of Yap/Taz/Yki was not associated with cell proliferation during development, and their experimental overactivation in hepatocytes and Drosophila retinal cells did not reactivate the precursor cell program
.
In contrast, Yap/Taz/Yaki is active and essential in specific cell types--- squamous peripodial epithelial cells and mouse cholangiocyte ---, whose overactivation induces an abnormal gene expression profile
that partially resembles the normal genetic program in these cells.
Finally, several target genes of the Hippo signaling pathway were identified in the functional screening of fruit flies, which are needed for ectopic overgrowth, but not for normal growth
.

Taken together, these data show that the Hippo signaling pathway does not guide normal organ growth, and that the classical Hippo mutant overgrowth phenotype represents the functional gain of Yap/Taz/Yki, which involves ectopic expression
of genes normally expressed in Hippo-dependent cell types.
Cells that require an output from the endogenous Hippo signaling pathway, such as squamous cells, have mechanical stress
.
Thus, the Hippo signaling pathway is involved in cell response to mechanical stress and morphologically challenged cell differentiation and homeostasis
.
These findings correct long-held misconceptions about the role of the Hippo signaling pathway in organ growth and reveal the need to reassess the understanding of its function in other contexts, such as in cancer and regeneration
.
(Biovalley Bioon.
com)

Resources:

W.
Kowalczyk et al.
 Hippo signaling instructs ectopic but not normal organ growth, Science, 2022, doi:10.
1126/science.
abg3679.