BDNF Promotes Axon Branching of Retinal Ganglion Cells via miRNA-132 and p250GAP

Abstract

A crucial step in the development of the vertebrate visual system is the branching of retinal ganglion cell (RGC) axons within their target, the superior colliculus/tectum. A major player in this process is the neurotrophin brain-derived neurotrophic factor (BDNF). However, the molecular basis for the signaling pathways mediating BDNF action is less well understood. As BDNF exerts some of its functions by controlling the expression of microRNAs (miRNAs), we investigated whether miRNAs are also involved in BDNF-mediated retinal axon branching. Here, we demonstrate that the expression pattern of miRNA-132 in the retina is consistent with its involvement in this process, and that BDNF induces the upregulation of miRNA-132 in retinal cultures. Furthermore, in vitro gain-of-function and loss-of-function approaches in retinal cultures reveal that miRNA-132 mediates axon branching downstream of BDNF. A known target of miRNA-132 is the Rho family GTPase-activating protein, p250GAP. We find that p250GAP is expressed in RGC axons and mediates the effects of miRNA-132 in BDNF-induced branching. BDNF treatment or overexpression of miRNA-132 leads to a reduction in p250GAP protein levels in retinal cultures, whereas the overexpression of p250GAP abolishes BDNF-induced branching. Finally, we used a loss-of-function approach to show that miRNA-132 affects the maturation of RGC termination zones in the mouse superior colliculus in vivo, while their topographic targeting remains intact. Together, our data indicate that BDNF promotes RGC axon branching during retinocollicular/tectal map formation via upregulation of miRNA-132, which in turn downregulates p250GAP.

MicroRNAs in neural development: from master regulators to fine-tuners

“…3A). In support of this, it has been reported that brain-derived neurotrophic factor (BDNF)-induced axonal branching in the developing mouse retina depends on increased levels of miR-132, which promotes axonal branching by inhibiting the translation of its known target Rho family GTPaseactivating protein, p250GAP (Arhgap32) (Marler et al, 2014). Increased levels of other miRNAs, such as miR-124 in hippocampal neurons (Franke et al, 2012) and miR-29a in cortical neurons (Li et al, 2014), can also induce axonal branching.…”

“…3B). For example, miR-132 was shown to regulate the dendritic growth and branching of mouse and chick young hippocampal neurons in vitro and in vivo by repressing p250GAP (Magill et al, 2010;Marler et al, 2014;Remenyi et al, 2013). Another activity-regulated miRNA, miR-134, was shown not be involved in dendritogenesis under normal growth conditions, but is specifically required for the activity-induced dendritic growth of cultured rat hippocampal neurons, acting by targeting the RNA-binding protein Pum2 in dendrites (Fiore et 2009).…”

MicroRNA-132 aggravates epileptiform discharges via suppression of BDNF/TrkB signaling in cultured hippocampal neurons

“…BDNF exerts potent effects on physiological and pathological mechanism of central nervous system by inducing the upregulation of miR-132, which has been widely recognized (Edbauer et al, 2010;Marler et al, 2014;Remenyi et al, 2010;Wanet et al, 2012). We tested if miR-132 might influence the expression of BDNF mRNA.…”

Targeted deletion of miR-132/-212 impairs memory and alters the hippocampal transcriptome

“…miR-132 regulates dendritic morphogenesis by Rac1-PAK signaling via p250GAP, which in turn affects synaptic plasticity (Wayman et al 2008;Impey et al 2010;Lambert et al 2010;Dhar et al 2014;Lesiak et al 2014). miR-132 has also been shown to be localized to axons and to regulate their extension via Rasa1 and p250GAP (Hancock et al 2014;Marler et al 2014). Deletion of the miR-132/-212 locus enhanced theta burst long-term potentiation (LTP), whereas overexpression of miR-132 in cultured hippocampal neurons limits synaptic depression following a train of stimuli while increasing the paired-pulse ratio Remenyi et al 2013).…”