Elk3 Deficiency Causes Transient Impairment in Post-Natal Retinal Vascular Development and Formation of Tortuous Arteries in Adult Murine Retinae

Abstract

Serum Response Factor (SRF) fulfills essential roles in post-natal retinal angiogenesis and adult neovascularization. These functions have been attributed to the recruitment by SRF of the cofactors Myocardin-Related Transcription Factors MRTF-A and -B, but not the Ternary Complex Factors (TCFs) Elk1 and Elk4. The role of the third TCF, Elk3, remained unknown. We generated a new Elk3 knockout mouse line and showed that Elk3 had specific, non-redundant functions in the retinal vasculature. In Elk3(−/−) mice, post-natal retinal angiogenesis was transiently delayed until P8, after which it proceeded normally. Interestingly, tortuous arteries developed in Elk3(−/−) mice from the age of four weeks, and persisted into late adulthood. Tortuous vessels have been observed in human pathologies, e.g. in ROP and FEVR. These human disorders were linked to altered activities of vascular endothelial growth factor (VEGF) in the affected eyes. However, in Elk3(−/−) mice, we did not observe any changes in VEGF or several other potential confounding factors, including mural cell coverage and blood pressure. Instead, concurrent with the post-natal transient delay of radial outgrowth and the formation of adult tortuous arteries, Elk3-dependent effects on the expression of Angiopoietin/Tie-signalling components were observed. Moreover, in vitro microvessel sprouting and microtube formation from P10 and adult aortic ring explants were reduced. Collectively, these results indicate that Elk3 has distinct roles in maintaining retinal artery integrity. The Elk3 knockout mouse is presented as a new animal model to study retinal artery tortuousity in mice and human patients.

MEF2 transcription factors are key regulators of sprouting angiogenesis

“…The challenge in understanding the phenotypes after Mef2 ablation comes because individual loss of different genes required during sprouting angiogenesis can result in vastly different consequences. While depletion of Dll4 levels can have a proangiogenic effect, loss or depletion of direct MEF2 targets ETS1, ELK3, and HLX can have anti-angiogenic effects in vivo (Pham et al 2007;Wei et al 2009;Herbert et al 2012;Weinl et al 2014). Furthermore, the vascular Notch pathway genes disregulated by DLL4 reduction are themselves, like all other vascular genes, likely to be direct ETS factor targets, suggesting that the hypersprouting routinely seen after Dll4 disruption may also be indirectly repressed by the general suppression of MEF2-ETS-Notch pathway gene activation.…”

Resolving the fibrotic niche of human liver cirrhosis using single-cell transcriptomics

“…Scar-associated endothelial cells displayed enhanced expression of the ELK3 regulon ( Fig. 4g), a transcription factor known to modulate angiogenesis 46 . Metagene signature analysis found that Endo(6) (SAEndo(1)) cells expressed fibrogenic genes including PDGFD, PDGFB, LOX, LOXL2 and several basement membrane components [47][48][49] ; associated significant ontology terms included extracellular matrix organization and wound healing (signature A; Extended Data Fig.…”

SRF Co-factors Control the Balance between Cell Proliferation and Contractility

“…Genetically, the TCFs are at least partly functionally redundant (Costello et al., 2010, Weinl et al., 2014) and may also function independently of SRF (Boros et al., 2009a, Boros et al., 2009b, Buchwalter et al., 2005). Although they have been implicated in proliferation and cancer (Vickers et al., 2004, Wozniak et al., 2012, Yang et al., 2012), the extent to which the immediate-early transcriptional response is TCF-dependent, and the target genes involved, has not been systematically investigated.…”