TEADs, Yap, Taz, Vgll4s transcription factors control the establishment of Left-Right asymmetry in zebrafish

Abstract

In many vertebrates, establishment of Left-Right (LR) asymmetry results from the activity of a ciliated organ functioning as the LR Organizer (LRO). While regulation of the formation of this structure by major signaling pathways has been described, the transcriptional control of LRO formation is poorly understood. Using the zebrafish model, we show that the transcription factors and cofactors mediating or regulating the transcriptional outcome of the Hippo signaling pathway play a pivotal role in controlling the expression of genes essential to the formation of the LRO including ligands and receptors of signaling pathways involved in this process and most genes required for motile ciliogenesis. Moreover, the transcription cofactor, Vgll4l regulates epigenetic programming in LRO progenitors by controlling the expression of writers and readers of DNA methylation marks. Altogether, our study uncovers a novel and essential role for the transcriptional effectors and regulators of the Hippo pathway in establishing LR asymmetry.

Eomesodermin is functionally conserved between zebrafish and mouse in spite of different mutant phenotypic severities, and controls left/right organiser formation via interlocking feedforward loops

“…Though Eomesa represses expression of vgll4l during blastula stages, during gastrulation vgll4l is expressed in DFCs, and has recently been identified as a key regulator of DFC proliferation, survival and function [13]. Repression of vgll4l at later stages in DFCs would consequently be inconsistent with promoting DFC formation.…”

“…Recent evidence suggests Vgll4l is required for tbx16 expression during DFC formation [13]. That Tbx16 binds the vgll4l promoter during gastrulation could suggest that complex regulatory loops control DFC formation and maintenance.…”

“…Eomesa is also sufficient to induce progenitors of the left/right organiser, known as dorsal forerunner cells (DFCs) in zebrafish [10]. However, we recently found that Eomesa represses expression of the transcriptional cofactor vgll4l [12], a key positive regulator of DFC proliferation, survival and function [13]. Here we further investigate these paradoxical findings.…”

Correction of the tumor suppressor Salvador homolog-1 deficiency in tumors by lycorine as a new strategy in lung cancer therapy

“…Activation of the upstream tumor suppressors Salvador homologue 1 (SAV1, also known as WW45) 4 , mammalian Ste20-like 1 and 2 (MST1/2) 5 , large tumor suppressor 1 and 2 (LATS1/2), and MOB kinase activators 6 in the Hippo pathway inhibits tumorigenesis. In contrast, escalation of the downstream oncoproteins, Yes-associated protein (YAP) 7 and transcriptional coactivator PDZ-binding motif (TAZ) 8 , in the pathway promotes tumorigenesis [9][10][11] . Deficiency of the tumor suppressors SAV1, MST1/2, LATS1/2, and MOB kinase activators in the Hippo pathway activates oncogenic YAP/ TAZ and causes carcinogenesis [9][10][11] .…”

“…In contrast, escalation of the downstream oncoproteins, Yes-associated protein (YAP) 7 and transcriptional coactivator PDZ-binding motif (TAZ) 8 , in the pathway promotes tumorigenesis [9][10][11] . Deficiency of the tumor suppressors SAV1, MST1/2, LATS1/2, and MOB kinase activators in the Hippo pathway activates oncogenic YAP/ TAZ and causes carcinogenesis [9][10][11] . SAV1 is at the front of the Hippo signal pathway (SAV1-MST1/2-LATS1/2-YAP/TAZ) and is required for the pathway activation [12][13][14][15][16] .…”