Small heat shock proteins Hspb7 and Hspb12 regulate early steps of cardiac morphogenesis

Abstract

Cardiac morphogenesis is a complex multi-stage process, and the molecular basis for controlling distinct steps remains poorly understood. Because gata4 encodes a key transcriptional regulator of morphogenesis, we profiled transcript changes in cardiomyocytes when Gata4 protein is depleted from developing zebrafish embryos. We discovered that gata4 regulates expression of two small heat shock genes, hspb7 and hspb12, both of which are expressed in the embryonic heart. We show that depletion of Hspb7 or Hspb12 disrupts normal cardiac morphogenesis, at least in part due to defects in ventricular size and shape. We confirmed that gata4 interacts genetically with the hspb7/12 pathway, but surprisingly, we found that hspb7 also has an earlier, gata4-independent function. Depletion perturbs Kupffer’s vesicle (KV) morphology leading to a failure in establishing the left-right axis of asymmetry. Targeted depletion of Hspb7 in the yolk syncytial layer is sufficient to disrupt KV morphology and also causes an even earlier block to heart tube formation and a bifid phenotype. Recently, several genome-wide association studies found that HSPB7 SNPs are highly associated with idiopathic cardiomyopathies and heart failure. Therefore, GATA4 and HSPB7 may act alone or together to regulate morphogenesis with relevance to congenital and acquired human heart disease.

T-REX on-demand redox targeting in live cells

“…72); and (iv) DCAF11—a mammalian analog of a stress-responsive protein in Caenorhabditis elegans . We also screened zebrafish HSPB7—a member of the small heat-shock protein family that is highly and selectively expressed in the heart 73,74 . hspb7 is not upregulated by heat shock 75 , and thus it probably has other regulation mechanisms that are as yet unidentified.…”

HSPB7 is indispensable for heart development by modulating actin filament assembly

“…Mutations found within the HSPB7 gene are associated with heart disease (19)(20)(21)(22). In zebrafish, loss-of-function studies showed that HSPB7 is essential for left-right asymmetry and cardiac morphogenesis (23,24). However, the role of HSPB7 in mammalian heart is still unclear.…”

Regulation of Hspb7 by MEF2 and AP-1: implications for Hspb7 in muscle atrophy

“…It would be interesting to further investigate this in the context of ageing or fasting. Hspb7 is highly expressed in the heart, and a crucial role for Hspb7 in heart development has been shown in zebrafish (Rosenfeld et al, 2013). Mutations in Hspb7 are correlated with cardiomyopathies and, co-incidentally, Hspb7 SNPs within the second intron (where GR and AP-1 recruitment was observed) are associated with cardiomyopathies (Garnier et al, 2015;Matkovich et al, 2010).…”

“…Hspb7 (also known as cvHsp) is highly expressed in skeletal and cardiac muscle (Krief et al, 1999) and has been linked to cardiac morphogenesis, cardiomyopathies and skeletal muscle integrity in the adult (Chiu et al, 2012;Juo et al, 2016;Rosenfeld et al, 2013). In other cell types, Hspb7 has been shown to prevent protein aggregation (Eenjes et al, 2016;Minoia et al, 2014) and to localize to nuclear speckles (Vos et al, 2009), a sub-nuclear location in which pre-mRNA is spliced.…”