Elk1 is an ETS Class I, TCF subfamily transcription factor known as a well- established downstream effector
of the MAPK pathway and has been implicated in the causation of a variety of cancers. Recent in-vitro
evidence places Elk1 in the context of the cardiogenic transcription factor network, although its in-vivo role
in cardiogenesis remains unexplored.
We provide the first in-vivo evidence of the role of Elk1 in cardiogenesis using a zebrafish mutant with
disrupted DNA binding domain (elk1 -543/-543) and cardiac defects including valve displacement and
elongation with hypertrophic/hyperplastic changes in the ventricular myocardium. elk1 -543/-543 are
predisposed to early embryonic death, with high incidence of heart looping defects and accelerated growth
among survivors.
RNA-seq at 6dpf provides insights into the basis of heart defects, indicating up-regulation of MAPK pathway
genes and down-regulation of trim63a, encoding a homeostatic protein involved in reducing muscle mass,
dys-regulation of which is associated with Hypertrophic Cardiomyopathy (HCM) in humans.
MAPK pathway up-regulation is commonly associated with HCM although the fundamental basis of this
relationship is not completely understood. We provide mechanistic insight, suggesting MAPK perturbations
could converge via the TCFs at a (putative) trim63a enhancer, down-regulating trim63a to mediate HCM.
Early developmental RNA-seq indicates loss of Elk1 function is associated with down-regulation of tumor
suppressor genes. We hypothesize this promotes embryonic survival via non-optimal pathways, and
fundamentally underlies observed defects.
The sum of changes in elk1 -543/-543 mimic a group of congenital syndromes known as “RASopathies" in
humans. Our data provides important insights into the time line of molecular events underlying
RASopathies/MAPK pathway defects and their relationship to molecules imperative in heart patterning and
homeostasis.