microRNA-24a is required to repress apoptosis in the developing neural retina

Abstract

Programmed cell death is important for the proper development of the retina, and microRNAs (miRNAs) may be critical for its regulation. Here, we report that miR24a is expressed in the neural retina and is required for correct eye morphogenesis in Xenopus. Inhibition of miR-24a during development causes a reduction in eye size due to a significant increase in apoptosis in the retina, whereas overexpression of miR-24a is sufficient to prevent apoptosis. We show that miR-24a negatively regulates the proapoptotic factors caspase9 and apaf1, demonstrating a role for miRNAs in the regulation of apoptosis during normal development. Programmed cell death, or apoptosis, regulates the size and morphology of developing tissues and organs, and this is particularly true in the developing neural retina. The neural retina gives rise to the photoreceptors, retinal ganglion cells, and the optic nerve, and as many as 90% of newborn retinal ganglion cells die during rat retinal development (de la Rosa and de Pablo 2000;Vecino et al. 2004). In Xenopus, spatiotemporal elimination of retinal cells is a key factor in maturation (Gaze and Grant 1992). In the chick, Caspase-dependent apoptosis has been demonstrated in the retina, and inhibition of Caspases results in an enlargement of the ganglion cell layer (Mayordomo et al. 2003). Similarly, in mice, apoptotic factors are highly expressed in the early retina and downregulated as development proceeds (O'Driscoll et al. 2006;Wallace et al. 2006), and knockdown of Caspases results in an overgrown retina (Hakem et al. 1998). However, the factors important for the regulation of Caspases and other apoptotic factors in the eye are unknown, although some transcriptional regulation has been postulated (Wallace et al. 2006). microRNAs (miRNAs), a class of regulatory noncoding RNA genes, have evolutionarily conserved roles during the development of many organs, including the heart and nervous system (Zhao et al. 2005;Makeyev et al. 2007). miRNAs are transcribed by RNA Polymerase II as primary miRNAs (pri-miRNAs). These transcripts are then processed by the enzymes Drosha and Dicer to generate the mature single-stranded miRNA of ;22 nucleotides, which is then incorporated into the RNA-induced silencing complex (RISC), characterized by the presence of the Argonaute family of proteins (Pasquinelli et al. 2005). This complex is responsible for the regulatory function of the miRNAs, leading to translational repression or degradation of target mRNAs.Several miRNAs have been implicated in the regulation of apoptosis in Drosophila (Xu et al. 2004). In various forms of cancer, miR-21 has been shown to be an antiapoptotic factor (Chan et al. 2005;Cheng et al. 2005) and miR-34 has been shown to be a downstream target of p53 and an inducer of cell death (He et al. 2007). However, knowledge is still lacking about the in vivo roles of most miRNAs during vertebrate development. Recent work in mice has shown that Dicer inactivation, specifically in the retina, results in neuronal degeneration (Damiani et al. 20...

Risk factors and biomarkers of age-related macular degeneration

“…In addition, miRNAs play an essential role in normal and abnormal development of the eye, like miR204 involvement in microphthalmia (Conte et al, 2010), cornea (Ryan et al, 2006), and retina (Li et al, 2009) (Vecino et al, 2004) (Walker and Harland, 2009) (Hackler et al, 2010) (Yan et al, 2010). In the retina, miRNAs are involved in regulation of retinal cell differentiation (Arora et al, 2010; Decembrini et al, 2009), including neuronal and retinal ganglion cell (RGC) development (Baudet et al, 2012).…”

MicroRNA-215 Regulates Fibroblast Function: Insights from a Human Fibrotic Disease

“…2 Alternatively, microRNAs may be found within gene sequences where they are generally transcribed together with their host genes. 2,3 MicroRNAs participate in a vast range of developmental and physiological processes, including fibrosis, 4,5 cell proliferation, 6 apoptosis, 7 differentiation, 8 metabolism, 9 and angiogenesis. 10 Because of their extensive involvement in cellular processes, derangement of microRNA is associated with disease formation such as in tumorigenesis, 11,12 inflammatory diseases 13,14 and defective neuronal development.…”

“…10 Because of their extensive involvement in cellular processes, derangement of microRNA is associated with disease formation such as in tumorigenesis, 11,12 inflammatory diseases 13,14 and defective neuronal development. 15 Nucleotide arrays [16][17][18][19][20] and other studies have detected microRNAs in the eye, 16,17 and elucidated their roles in development and differentiation [16][17][18] of the retina, 7,19,21 lens 20 and cornea. 16 In humans, microRNAs have been implicated in various diseases, 11,[22][23][24] including neovascularization 25 and fibrosis.…”

miRNA-182 and the regulation of the glioblastoma phenotype - toward miRNA-based precision therapeutics

“…Furhtermore, miR-125b and miR-24a have been implicated in regulating apoptosis during neural development by regulating p53 and other apoptosis effector proteins. 19,20 Reflecting their roles in CNS development, deregulated miRNA expression drives or contributes to the development of malignant brain cancers, in particular GBM. Multiple miRNAs are differentially expressed in GBM vs. normal brain tissue, and target key molecules with central functions in angiogenesis, glioma cell proliferation, invasion and susceptibility toward extant therapies.…”