Regenerative neurogenic response from glia requires insulin-driven neuron-glia communication

Abstract

Understanding how injury to the Central Nervous System (CNS) induces de novo neurogenesis in animals would help promote regeneration in humans. Regenerative neurogenesis could originate from glia and glial Neuron-Glia antigen-2 (NG2) may sense injury-induced neuronal signals, but these are unknown. Here, we used Drosophila to search for genes functionally related the NG2 homologue kon-tiki (kon), and identified Islet Antigen-2 (Ia-2), required in neurons for insulin secretion. Alterations in Ia-2 function induced neural stem cell gene expression, injury increased ia-2 expression and induced ectopic neural stem cells. Using genetic analysis and lineage tracing, we demonstrate that Ia-2 and Kon regulate Drosophila insulin-like peptide 6 (Dilp-6), to induce glial proliferation and neural stem cells from glia. Ectopic neural stem cells can divide, and limited de novo neurogenesis could be traced back to glial cells. Altogether, Ia-2 and Dilp-6 drive a neuron-glia relay that restores glia, and reprograms glia into neural stem cells for regeneration.

Insights into nervous system repair from the fruit fly

“…However, it is generally accepted that proliferation in the adult brain is triggered in response to injury ( Figure 2 ). This occurs not only in glial cells, producing new neurons and glia [ 30 , 87 , 90 ] but also in cells negative for glial and neuronal markers but positive for Deadpan (Dpn), a transcription factor and stemness marker ( Table 1 ) that becomes nuclear localized upon injury [ 31 , 34 ]. These adult cells, which behave similarly to quiescent NSCs, have been detected in the optic lobe and the central brain.…”

“…Recently, Islets antigen-2 (Ia-2) , which is exclusively expressed in neurons, has been shown to genetically interact with kon , exclusively expressed in glia [ 90 ]. This glial-neuronal communication has been implicated in glio- and neurogenesis response to CNS injury ( Figure 2 ), but the mode of interaction is currently unknown.…”

“…Dpn expression in NG2-like glia confers neural stem cell-like capacity to these glial cells. The newly created glial-derived NSCs can divide to produce a very limited number of glia and neurones [ 90 ].…”

Regenerative Strategies for Retinal Neurons: Novel Insights in Non-Mammalian Model Organisms

“…Remarkably, regeneration by glycolytic metabolites signaling is retained in mammals. In addition, Notch and the chondroitin sulfate proteoglycan NG2 homolog called Kon promoted glial proliferation in drosophila, similar to vertebrates [ 49 ]. In particular, Kon induced glia differentiation and the expression of prospero, thus maintaining proliferation.…”

Novel Approaches Used to Examine and Control Neurogenesis in Parkinson′s Disease

“…Particularly, insulin may enhance dopamine release in the striatum through cholinergic interneurons [231]. Data obtained in Drosophila reveal that the induction of NSCs from glia, their proliferation and limited neurogenesis are regulated by insulin signaling [232]. Neurogenesis in conventional neurogenic niches (SVZ and SGZ) also depends on insulin and insulin-like growth factors (IGF) [233]; thus, cerebral insulin resistance evident in chronic neurodegeneration (Alzheimer's disease, Parkinson's disease) negatively affects neurogenesis [234], whereas peptides facilitating insulin effects promote the development of new dopaminergic neurons in SN in a model of PD [235].…”