Gene network underlying the glial regenerative response to central nervous system injury

Abstract

Although the central nervous system does not regenerate, injury induces repair and regenerative responses in glial cells. In mammals, activated microglia clear up apoptotic cells and debris resulting from the injury, astrocytes form a scar that contains the lesion, and NG2-glia elicit a prominent regenerative response. NG2-glia regenerate themselves and differentiate into oligodendrocytes, which remyelinate axons leading to some recovery of locomotion. The regenerative response of glial cells is evolutionarily conserved across the animals and Drosophila genetics revealed an underlying gene network. This involves the genes Notch, kon-tiki, eiger, dorsal, and prospero, homologues of mammalian Notch1, ng2, TNF, NFjB, and prox1, respectively. Feedback loops between these genes enable a surge in proliferation in response to injury and ensuing differentiation. Negative feedback sets a timer for proliferation, and prevents uncontrolled growth that could lead to glioma. Remarkable parallels are found in these genetic relationships between fruit flies and mammals. Drosophila findings provide insights into gene functions that could be manipulated in stem cells and progenitors for therapeutic repair. Developmental Dynamics 247:85-93, 2018. V C 2017 Wiley Periodicals, Inc.

Social reprogramming in ants induces longevity-associated glia remodeling

“…Single-cell RNA-seq can only provide relative numbers, and therefore we cannot formally exclude that the apparent specific expansion of ensheathing glia in gamergates is the result of a simultaneous loss in absolute numbers of most of the other brain cell types, however the most parsimonious explanation is that ensheathing glia respond to caste reprogramming by increasing in numbers, most likely via proliferation. It is known that insect glia proliferates in response to injury 85,100,101,114 , but to our knowledge this is the first observation of a programmed, regulated expansion of a glia subset in otherwise healthy 14 brains. We detected caste-specific differences in the expression of a majority of ensheathing markers in three other social insects ( Fig.…”

“…In the mammalian brain, phagocytic microglia cells proliferate and migrate to sites of injury and are involved in clearing damaged tissue, modulating inflammation, and promoting remyelination in concert with oligodendrocyte precursors [95][96][97][98] . In Drosophila brains, these phagocytic and repair functions are carried out by ensheathing glia cells, which combine features of microglia and oligodendrocytes and activate conserved transcriptional networks and molecular pathways following injury 82,[99][100][101] .…”

Dpp and Hedgehog promote the Glial response to neuronal damage in the developing Drosophila Visual system

“…The c-Jun N-terminal kinase (JNK) pathway plays a fundamental role in regulating many biological processes involved in regeneration, including activation of glial response to damage in the CNS (Kato et al, 2018;Lu et al, 2017;Kato et al, 2011). Moreover, it has been proposed that in developing eye discs the ectopic activation of this pathway in the cells anterior to the morphogenetic furrow is sufficient to induce matrix metalloproteinase 1 (Mmp1) expression and trigger glia over-migration (Tavares et al, 2017).…”

“…However, the use of the eye disc as a model system to study glial response to neuronal damage and the mechanisms that might be regulating them, has remained largely unexplored. Glial regenerative response (GRR) is found across many species and may reflect a common underlying genetic mechanism (Hidalgo and Logan, 2017;Kato et al, 2018). Considering that Drosophila glia cells have served as an experimental model to gain insights into mammalian glial biology, eye discs might provide an excellent model system to discover evolutionarily conserved signalling networks regulating glia regenerative response.…”

“…Glial cells actively participate in all aspects of nervous system development, including the mechanism involved in maintaining structural robustness and functional plasticity. In response to neuronal damage, glial cells proliferate, change their morphology and alter their behaviour (Kato et al, 2018;Klambt, 2009;Brosius Lutz and Barres, 2014). This glial cell response is associated with their regenerative function and is found across species.…”