Planarian yorkie/YAP functions to integrate adult stem cell proliferation, organ homeostasis and maintenance of axial patterning

Abstract

During adult homeostasis and regeneration, the freshwater planarian must accomplish a constant balance between cell proliferation and cell death, while also maintaining proper tissue and organ size and patterning. How these ordered processes are precisely modulated remains relatively unknown. Here we show that planarians use the downstream effector of the Hippo signaling cascade, yorkie (yki; YAP in vertebrates) to control a diverse set of pleiotropic processes in organ homeostasis, stem cell regulation, regeneration and axial patterning. We show that yki functions to maintain the homeostasis of the planarian excretory (protonephridial) system and to limit stem cell proliferation, but does not affect the differentiation process or cell death. Finally, we show that Yki acts synergistically with WNT/β-catenin signaling to repress head determination by limiting the expression domains of posterior WNT genes and that of the WNTinhibitor notum. Together, our data show that yki is a key gene in planarians that integrates stem cell proliferation control, organ homeostasis, and the spatial patterning of tissues.

Wnt/Notum spatial feedback inhibition controls neoblast differentiation to regulate reversible growth of the planarian brain

“…Mammalian wnt1, wnt3a and wnt8 participate in brain patterning and proliferation (Erter et al, 2001;Lee et al, 2000;McMahon and Bradley, 1990;Thomas and Capecchi, 1990), but the precise mechanisms that relate Wnt ligands and secreted inhibitors for control of brain size remain unclear in vertebrates, as do their relationships with additional regulatory pathways. Perturbation of planarian insulin (Miller and Newmark, 2012) or hippo signaling (Lin and Pearson, 2014) causes body-wide defects in neoblast proliferation, suggesting that alternative pathways are used for control of brain size. Our results reveal a broadly conserved relationship between Wnt activity and brain size and suggest that the planarian brain is a tractable system for discovery of additional size regulatory pathways.…”

Reconsidering regeneration in metazoans: an evo-devo approach

“…The Hippo pathway, and its effectors YAP and TAZ, act as mediators of other protein signaling pathways that influence cell-fate, proliferation, apoptosis, cell shape and cell movement. However, the same molecules also have a role in regulating stem cell self-renewal and expansion in regenerative processes in different phyla (Zhao et al, 2011;Demircan and Berezikov, 2013;Johnson and Halder, 2014;Lin and Pearson, 2014). Wnt, BMP and Nodal represent the signaling pathways defining the body axes during embryonic development, at least in bilaterians.…”

Indeterminate Growth: Could It Represent the Ancestral Condition?

“…Interestingly, recent studies have noted that, unlike for many other organs, inactivation of Yap/ Yki, the growth-promoting transcriptional coactivator, in either the mouse intestine or in planarians results in an increase in the number of stem cells (Barry et al 2013;Lin and Pearson 2014). The ability to shrink is also observed in the vertebrate intestine, most remarkably in those of snakes, such as the python, which intermittently feed on whole animals often months apart (Secor and Diamond 1997).…”