Negative Fgf8-Bmp2 feed-back is regulated by miR-130 during early cardiac specification

Abstract

It is known that secreted proteins from the anterior lateral endoderm, FGF8 and BMP2, are involved in mesodermal cardiac differentiation, which determines the first cardiac field, defined by the expression of the earliest specific cardiac markers Nkx-2.5 and Gata4. However, the molecular mechanisms responsible for early cardiac development still remain unclear. At present, microRNAs represent a novel layer of complexity in the regulatory networks controlling gene expression during cardiovascular development. This paper aims to study the role of miR130 during early cardiac specification. Our model is focused on developing chick at gastrula stages. In order to identify those regulatory factors which are involved in cardiac specification, we conducted gain- and loss-of-function experiments in precardiac cells by administration of Fgf8, Bmp2 and miR130, through in vitro electroporation technique and soaked beads application. Embryos were subjected to in situ hybridization, immunohistochemistry and qPCR procedures. Our results reveal that Fgf8 suppresses, while Bmp2 induces, the expression of Nkx-2.5 and Gata4. They also show that Fgf8 suppresses Bmp2, and vice versa. Additionally, we observed that Bmp2 regulates miR-130 -a putative microRNA that targets Erk1/2 (Mapk1) 3'UTR, recognizing its expression in precardiac cells which overlap with Erk1/2 pattern. Finally, we evidence that miR-130 is capable to inhibit Erk1/2 and Fgf8, resulting in an increase of Bmp2, Nkx-2.5 and Gata4. Our data present miR-130 as a necessary linkage in the control of Fgf8 signaling, mediated by Bmp2, establishing a negative feed-back loop responsible to achieve early cardiac specification.

Four microRNAs Signature for Survival Prognosis in Colon Cancer using TCGA Data

“…The authors suggested the miR-130 family could be a promising therapeutic target for invasive bladder cancer. Some other studies revealed miR-130 also participated in cardiac development and pulmonary hypertension2122. So far, rare study focused on miR-130a in colon cancer.…”

Interdigital tissue remodelling in the embryonic limb involves dynamic regulation of the miRNA profiles

“…; Jafarzadeh & Soltani, ), and miR‐140‐5p and miR‐130 modulate BMP2 signalling in embryonic vertebrates (Lopez‐Sanchez et al. ; Gan et al. ).…”

“…In developing systems, miRNAs show specific temporal and spatial expression patterns (Ahmed et al 2015), and have been functionally implicated in events requiring cell fate determination. The numerous developmental processes involving an active role of miRNAs include gametogenesis, preimplantation and early embryonic stages, neurogenesis and somitogenesis (Ahmed et al 2015;Lopez-Sanchez et al 2015;Bhattacharya et al 2016). However, the association of developmental defects with miRNA mutations in humans and other mammals is rare (de Pontual et al 2011;Parchem et al 2015;Yang et al 2015).…”

“…In addition to the direct regulation of the apoptotic molecular cascades, the regulation of apoptosis by miRNAs can be mediated by the indirect targeting of regulatory signals, which in turn regulate cell death. Notably, various miRNAs such as miR-21 or miR-590-5p, modulate intracellular effectors of TGFb signalling (Li et al 2013;Lan et al 2014;Jafarzadeh & Soltani, 2016), and miR-140-5p and miR-130 modulate BMP2 signalling in embryonic vertebrates (Lopez-Sanchez et al 2015;Gan et al 2016). Furthermore, miRNAs may also be involved in DNA damage and in senescence, which are degradative processes associated with embryonic programmed cell death (Lorda-Diez et al 2015a;Montero et al 2016).…”

Making a heart: advances in understanding the mechanisms of cardiac development

“…MicroRNAs (miRs) tend to mediate their effects by inducing RNA degradation. Recent studies defining specific roles of miRs included stimulation of cardiomyocyte proliferation (miR-410 and miR-495) [34], linkage of BMP signaling to regulate early cardiac specification (miR130) [35], and inhibition of epithelial to mesenchymal transition in the avian atrioventricular canal (miRs 23b, 199a, and 15a) [36]. Other studies of miRs have focused on expression patterns in specific disease states, looking at patterns of expression and beginning to correlate these to function.…”