Cardiac hypertrophy induced by active Raf depends on Yorkie-mediated transcription

Abstract

Organ hypertrophy can result from enlargement of individual cells or from cell proliferation or both. Activating mutations in the serine-threonine kinase Raf cause cardiac hypertrophy and contribute to Noonan syndrome in humans. Cardiac-specific expression of activated Raf also causes hypertrophy in Drosophila melanogaster. We found that Yorkie (Yki), a transcriptional coactivator in the Hippo pathway that regulates organ size, is required for Raf-induced cardiac hypertrophy in flies. Although aberrant activation of Yki orthologs stimulates cardiac hyperplasia in mice, cardiac-specific expression of an activated mutant form of Yki in fruit flies caused cardiac hypertrophy without hyperplasia. Knockdown of Yki caused cardiac dilation without loss of cardiomyocytes and prevented Raf-induced cardiac hypertrophy. In flies, Yki-induced cardiac hypertrophy required the TEA domain–containing transcription factor Scalloped, and, in mammalian cells, expression of mouse RafL613V, an activated form of Raf with a Noonan syndrome mutation, increased Yki-induced Scalloped activity. Furthermore, overexpression of Tgi (a Tondu domain–containing Scalloped-binding corepressor) in the fly heart abrogated Yki- or Raf-induced cardiac hypertrophy. Thus, crosstalk between Raf and Yki occurs in the heart and can influence Raf-mediated cardiac hypertrophy.

Fizzy-Related dictates A cell cycle switch during organ repair and tissue growth responses in the Drosophila hindgut

“…One possibility that we considered is that, in response to pro-growth signaling, endocycles may be better at preserving tissue architecture than mitotic cycles. Activation of the pro-growth signaling Ras pathway, which is well-known to drive cell number increases in many contexts, is also linked to ploidy increases in cardiac tissue in flies and mammals ( Hunter et al, 1995 ; Wu et al, 2011 ; Yu et al, 2015 ). We thus examined if constitutive activation of the small GTPase Ras ( Ras V12 ) could be used as an experimental tool to ask whether a tissue undergoing endocycles or mitotic cycles responds differently under conditions of sustained tissue growth signaling.…”

“…Injured mammalian hearts alter their cell cycle programming from mitotic to ploidy-increasing cell cycles during defined periods in development ( Porrello et al, 2011 ). As a result, cardiac cells typically undergo hypertrophy instead of hyperplasia in response to injury or sustained tissue growth signals such as from the Ras/Raf pathway ( Hunter et al, 1995 ; Porrello et al, 2011 ; Wu et al, 2011 ; Yu et al, 2015 ). In the liver, injury can cause either mitotic or ploidy-increasing cell cycle responses ( Gentric et al, 2015 ; Miyaoka et al, 2012 ; Nagy et al, 2001 ).…”

Redirecting cardiac growth mechanisms for therapeutic regeneration

“…Although increased YAP activity likely favors hyperplastic growth under homeostatic conditions in the adult mammalian heart, this bias towards cardiomyocyte hyperplasia over hypertrophy has not been demonstrated during pathologic states, such as after MI in adult mice (126,129,130). Other studies have associated excess YAP activity with hypertrophy (133)(134)(135). Nonetheless, modulation of the Hippo-YAP axis is a promising approach for achieving adult mammalian heart regeneration.…”

RASopathies: unraveling mechanisms with animal models

“…(A) Neurofibromatosis type 1 (NF1): 1994 ( Brannan et al, 1994 ), 1997 ( Silva et al, 1997 ; The et al, 1997 ), 1999 ( Cichowski et al, 1999 ), 2000 ( Guo et al, 2000 ), 2001 ( Williams et al, 2001 ; Zhu et al, 2001 ), 2002 ( Costa et al, 2002 ; Tong et al, 2002 ), 2003 ( Bajenaru et al, 2003 ), 2007 ( Ho et al, 2007 ; Kolanczyk et al, 2007 ), 2008 ( Cui et al, 2008 ), 2009 ( Padmanabhan et al, 2009 ), 2012 ( Shin et al, 2012 ; Wang et al, 2012 ), 2013 ( Walker et al, 2013 ), 2014 ( Diggs-Andrews et al, 2014 ). (B) Noonan syndrome (NS) and Noonan syndrome with multiple lentigines (NSML): 2004 ( Araki et al, 2004 ), 2006 ( Oishi et al, 2006 ), 2007 ( Jopling et al, 2007 ; Nakamura et al, 2007 ), 2009 ( Oishi et al, 2009 ; Pagani et al, 2009 ), 2010 ( Chen et al, 2010 ), 2011 ( Wu et al, 2011 ), 2012 ( De Rocca Serra-Nédélec et al, 2012 ; Razzaque et al, 2012 ), 2013 ( Aoki et al, 2013 ; Yu et al, 2013b ), 2014/15 ( Hernández-Porras et al, 2014 ; Vissers et al, 2015 ; Yu et al, 2015 ). (C) Cardio-facio-cutaneous syndrome (CFC) and Costello syndrome (CS): 2008 ( Schuhmacher et al, 2008 ), 2009 ( Anastasaki et al, 2009 ; Chen et al, 2009 ; Santoriello et al, 2009 ; Viosca et al, 2009 ), 2011 ( Urosevic et al, 2011 ), 2012 ( Anastasaki et al, 2012 ), 2014 ( Dalin et al, 2014 ; Goodwin et al, 2014 ).…”