Evolutionary Conservation of the Gcm/Glide Cascade: Of Glia and Beyond.

Background: Glia represent a major cell population of the nervous system, and they take part in virtually any process sustaining the development, the functioning, and the pathology of the nervous system. Glial cells diversified significantly during evolution and distinct signals have been adopted to initiate glial development in mammals as compared to flies. In the invertebrate model Drosophila melanogaster, the transcription factor Gcm is necessary and sufficient to generate glial cells. Although Gcm orthologs have been found in protostomes and deuterostomes, they do not act in glial fate commitment as in flies, calling for further investigations of the evolutionarily conserved role of Gcm.

Summary: Here, we review the impact of the fly Gcm transcription factor in the differentiation of phagocytic competent cells inside and outside the nervous system, glia, and macrophages, respectively. Then, we discuss the evolutionary conservation of Gcm and the neural/nonneural functions of Gcm orthologs. Finally, we present a recent work from Pavlidaki et al. [Cell Rep. 2022;41(3):111506] showing that the Gcm cascade is conserved from fly macrophages to mammalian microglia to counteract acute and chronic inflammation.

Key Messages: Gcm has an ancestral role in immunity, and its anti-inflammatory effect is evolutionarily conserved. This opens new avenues to assess Gcm function in other species/animal models, its potential involvement in inflammation-related processes, such as regeneration, and to expand the investigation on glia evolution.