Conserved microRNA pathway regulates developmental timing of retinal neurogenesis

Abstract

Most regions of the vertebrate central nervous system develop by the sequential addition of different classes of neurons and glia. This phenomenon has been best characterized in laminated structures like the retina and the cerebral cortex, in which the progenitor cells in these structures are thought to change in their competence as development proceeds to generate different types of neurons in a stereotypic sequence that is conserved across vertebrates. We previously reported that conditional deletion of Dicer prevents the change in competence of progenitors to generate later-born cell types, suggesting that specific microRNAs (miRNAs) are required for this developmental transition. In this report, we now show that three miRNAs, let-7, miR-125, and miR-9, are key regulators of the early to late developmental transition in retinal progenitors: (i) members of these three miRNA families increase over the relevant developmental period in normal retinal progenitors; (ii) inhibiting the function of these miRNAs produces changes in retinal development similar to Dicer CKO; (iii) overexpression of members of these three miRNA families in Dicer-CKO retinas can rescue the phenotype, allowing their progression to late progenitors; (iv) overexpression of these miRNAs can accelerate normal retinal development; (v) microarray and computational analyses of Dicer-CKO retinal cells identified two potential targets of the late-progenitor miRNAs: Protogenin (Prtg) and Lin28b; and (vi) overexpression of either Lin28 or Prtg can maintain the early progenitor state. Together, these data demonstrate that a conserved miRNA pathway controls a key step in the progression of temporal identity in retinal progenitors.heterochronic | progenitor competence

Onecut1 and Onecut2 redundantly regulate early retinal cell fates during development

“…Conceivably, transition from the early to late competence would involve repression of the onecut factors. Several factors, including Lhx2 and a group of microRNAs (let-7, miR-125, and miR-9), have been identified to be involved in this transition (6,7). Interestingly, all of the onecut genes are subject to repression by the microRNAs involved in the early-to-late transition (7), further supporting the important roles that the onecut factors play in generation of the early retinal cell types.…”

“…For example, deletion of the Lim-homeodomain gene Lhx2 leads to prolonged production of the early retinal cell-type RGCs (6). Similarly, a group of microRNAs (let-7, miR-125, and miR-9) has also been shown to be required for this transition from the early phase to the late phase (7). However, it is not clear what defines the early and late competence and whether shared mechanisms coordinate the births of all of the early or late cell fates.…”

The RNA-binding protein LIN28B regulates developmental timing in the mammalian cochlea

“…timing of retinal neurogenesis (26). Here, using recently developed iLIN28B and ilet-7g transgenic mouse lines (27), we show that Lin28b functions as a developmental timer in the murine cochlea through both let-7-dependent and let-7-independent mechanisms.…”

Lin28a uses distinct mechanisms of binding to RNA and affects miRNA levels positively and negatively

“…Expression of miRNA-9 is switched on during mid-embryogenesis after the development of the neuronal scaffold and is associated with active neurogenic areas (Darnell et al 2006;Walker and Harland 2008;Coolen et al 2012). MiRNA-9 is generally excluded from brain regions containing undifferentiated neuronal progenitors and from areas with late differentiation onset, such as the midbrain-hindbrain region and the retina (Leucht et al 2008;La Torre et al 2013). Moreover, REST and CREB regulate the transcription of miRNA-9 primary transcripts (Laneve et al 2010).…”