Evidence of Müller glia conversion into retina ganglion cells using Neurogenin2

Abstract

Macular Degeneration, Glaucoma, and Retinitis Pigmentosa are all leading causes of irreversible visual impairment in the elderly, affecting hundreds of millions of patients. Müller glia cells (MGC), the main type of glia found in the vertebrate retina, can resume proliferation in the adult injured retina and contribute to tissue repair. Also, MGC can be genetically reprogrammed through the expression of the transcription factor (TF) Achaete-scute homolog 1 (ASCL1) into induced neurons (iNs), displaying key hallmarks of photoreceptors, bipolar and amacrine cells, which may contribute to regenerate the damaged retina. Here, we show that the TF neurogenin 2 (NEUROG2) is also sufficient to lineage-reprogram MGC into iNs. The efficiency of MGC lineage conversion by NEUROG2 is similar to that observed after expression of ASCL1. However, reprogramming efficiency is affected by previous exposure to EGF and FGF2 during the expansion of MGC population. Transduction of either Neurog2 or Ascl1 led to the upregulation of key retina neuronal genes in MGC-derived iNs, but only NEUROG2 induced a consistent increase in the expression of putative retinal ganglion cell (RGC) genes. In vivo electroporation of Neurog2 in the neonatal retina also induced a shift in the generation of retinal cell subtypes, favoring the differentiation RGCs at the expense of MGCs. Altogether, our data indicate that Neurog2 induces lineage conversion of MGCs into RGC-like iNs.

An insight on established retinal injury mechanisms and prevalent retinal stem cell activation pathways in vertebrate models

“…184,185 Neurogenin-2, a basic helix-loop-helix (bHLH) transcription factor, is another potential candidate that activates MG regeneration. 186 Taking hints from regenerative models, many growth factors have been identified that help stimulate MG differentiation in mammals. These include retinoic acid, FGF, insulin, epidermal growth factor (EGF), HB-EGF, and progranulin.…”

Excitatory neurotransmission activates compartmentalized calcium transients in Müller glia without affecting lateral process motility

“…Across developmental steps from neurogenesis to circuit maturation, glia monitor their environment and in turn regulate neuronal production, migration, and differentiation, promote synapse turnover, and regulate synaptic function via neurotransmitter uptake and ion buffering 1 . In the vertebrate retina, for example, Müller glia exhibit neurogenic potential [2][3][4] , promote circuit-specific wiring via secretion of synaptogenic molecules 5 , regulate phagocytosis of neuronal debris 6 , and limit neurotransmitter spillover via transporter activity 7 .…”