Cell type-specific role of CBX2 and its disordered region in spermatogenesis.

Polycomb group (PcG) proteins maintain the repressed state of lineage-inappropriate genes and are therefore essential for embryonic development and adult tissue homeostasis. One critical function of PcG complexes is modulating chromatin structure. Canonical Polycomb repressive complex 1 (cPRC1), particularly its component CBX2, can compact chromatin and phase-separate in vitro. These activities are hypothesized to be critical for forming a repressed physical environment in cells. While much has been learned by studying these PcG activities in cell culture models, it is largely unexplored how cPRC1 regulates adult stem cells and their subsequent differentiation in living animals. Here, we show in vivo evidence of a critical nonenzymatic repressive function of cPRC1 component CBX2 in the male germline. CBX2 is up-regulated as spermatogonial stem cells differentiate and is required to repress genes that were active in stem cells. CBX2 forms condensates (similar to previously described Polycomb bodies) that colocalize with target genes bound by CBX2 in differentiating spermatogonia. Single-cell analyses of mosaic Cbx2 mutant testes show that CBX2 is specifically required to produce differentiating A1 spermatogonia. Furthermore, the region of CBX2 responsible for compaction and phase separation is needed for the long-term maintenance of male germ cells in the animal. These results emphasize that the regulation of chromatin structure by CBX2 at a specific stage of spermatogenesis is critical, which distinguishes this from a mechanism that is reliant on histone modification.

Cd59 and inflammation regulate Schwann cell development.

Efficient neurotransmission is essential for organism survival and is enhanced by myelination. However, the genes that regulate myelin and myelinating glial cell development have not been fully characterized. Data from our lab and others demonstrates that cd59, which encodes for a small GPI-anchored glycoprotein, is highly expressed in developing zebrafish, rodent, and human oligodendrocytes (OLs) and Schwann cells (SCs), and that patients with CD59 dysfunction develop neurological dysfunction during early childhood. Yet, the function of Cd59 in the developing nervous system is currently undefined. In this study, we demonstrate that cd59 is expressed in a subset of developing SCs. Using cd59 mutant zebrafish, we show that developing SCs proliferate excessively and nerves may have reduced myelin volume, altered myelin ultrastructure, and perturbed node of Ranvier assembly. Finally, we demonstrate that complement activity is elevated in cd59 mutants and that inhibiting inflammation restores SC proliferation, myelin volume, and nodes of Ranvier to wildtype levels. Together, this work identifies Cd59 and developmental inflammation as key players in myelinating glial cell development, highlighting the collaboration between glia and the innate immune system to ensure normal neural development.

The nervous system of vertebrates is made of up of complex networks of nerve cells that send signals to one another. In addition to these cells, there are a number of supporting cells that help nerves carry out their role. Schwann cells, for example, help nerve cells to transmit information faster by wrapping their long extensions in a fatty membrane called myelin. When myelin is not produced properly, this can disturb the signals between nerve cells, leading to neurological defects. Schwann cells mature simultaneously with nerve cells in the embryo. However, it was not fully understood how Schwann cells generate myelin during development. To investigate, Wiltbank et al. studied the embryos of zebrafish, which, unlike other vertebrates, are transparent and develop outside of the womb. These qualities make it easier to observe how cells in the nervous system grow in real-time using a microscope. First, the team analyzed genetic data collected from the embryo of zebrafish and mice to search for genes that are highly abundant in Schwann cells during development. This led to the discovery of a gene called cd59, which codes for a protein that also interacts with the immune system. To find out whether Schwann cells rely on cd59, Wiltbank et al. deleted the cd59 gene in zebrafish embryos. Without cd59, the Schwann cells produced too many copies of themselves and this, in turn, impaired the appropriate production of myelin. Since the protein encoded by cd59 normally balances inflammation levels, it was possible that losing this gene overactivated the immune system in the zebrafish embryos. In support of this hypothesis, when the cd59 mutant embryos were treated with an anti-inflammatory drug, this corrected Schwann cell overproduction and restored myelin formation. Taken together, these findings reveal how inflammation helps determine the number of Schwann cells produced during development, and that cd59 prevents this process from getting carried away. This suggests that the nervous system and immune system may work together to build the nervous system. In the future, it will be interesting to investigate whether cd59 acts in a similar way during the development of the human nervous system.

The multifactorial roles of microglia and macrophages in the maintenance and progression of glioblastoma.

The functional characteristics of glial cells, in particular microglia, have attained considerable importance in several diseases, including glioblastoma, the most hostile and malignant type of intracranial tumor. Microglia performs a highly significant role in the brain's inflammatory response mechanism. They exhibit anti-tumor properties via phagocytosis and the activation of a number of different cytotoxic substances. Some tumor-derived factors, however, transform these microglial cells into immunosuppressive and tumor-supportive, facilitating survival and progression of tumorigenic cells. Glioma-associated microglia and/or macrophages (GAMs) accounts for a large proportion of glioma infiltrating cells. Once within the tumor, GAMs exhibit a distinct phenotype of initiation that subsequently supports the growth and development of tumorigenic cells, angiogenesis and stimulates the infiltration of healthy brain regions. Interventions that suppress or prohibit the induction of GAMs at the tumor site or attenuate their immunological activities accommodating anti-tumor actions are likely to exert positive impact on glioblastoma treatment. In the present paper, we aim to summarize the most recent knowledge of microglia and its physiology, as well as include a very brief description of different molecular factors involved in microglia and glioblastoma interplay. We further address some of the major signaling pathways that regulate the baseline motility of glioblastoma progression. Finally, we discussed a number of therapeutic approaches regarding glioblastoma treatment.