Loss of Serpin E2 alters antimicrobial gene expression by microglia but not astrocytes.

Microglia are the brain-resident immune cells responsible for surveilling and protecting the central nervous system. These cells can express a wide array of immune genes, and that expression can become highly dynamic in response to changes in the environment, such as traumatic injury or neurological disease. Though microglial immune responses are well studied, we still do not know many mechanisms and regulators underlying all the varied microglial responses. Serpin E2 is a serine protease inhibitor that acts on a wide variety of serine proteases, with particularly potent affinity for the blood clotting enzyme thrombin. In the brain, Serpin E2 is highly expressed by many cell types, especially glia, and loss of Serpin E2 leads to behavioral changes as well as deficits in synaptic plasticity. To determine whether Serpin E2 is important for maintaining homeostasis in glia, we performed RNA sequencing of microglia and astrocytes from Serpin E2-deficient mice in a healthy state or under immune activation due to lipopolysaccharide (LPS) injection. We found that microglia in Serpin E2-deficient mice had higher expression of antimicrobial genes, while astrocytes did not display any robust changes in transcription. Furthermore, the lack of Serpin E2 did not affect transcriptional responses to LPS in either microglia or astrocytes. Overall, we find that Serpin E2 is a regulator of antimicrobial genes in microglia.

Prdm16 and Vcam1 regulate the postnatal disappearance of embryonic radial glia and the ending of cortical neurogenesis.

Embryonic neural stem cells (NSCs, i.e., radial glia) in the ventricular-subventricular zone (V-SVZ) generate the majority of neurons and glia in the forebrain. Postnatally, embryonic radial glia disappear and a subpopulation of radial glia transition into adult NSCs. As this transition occurs, widespread neurogenesis in brain regions such as the cerebral cortex ends. The mechanisms that regulate the postnatal disappearance of radial glia and the ending of embryonic neurogenesis remain poorly understood. Here, we show that PR domain-containing 16 (Prdm16) promotes the disappearance of radial glia and the ending of neurogenesis in the cerebral cortex. Genetic deletion of Prdm16 from NSCs leads to the persistence of radial glia in the adult V-SVZ and prolonged postnatal cortical neurogenesis. Mechanistically, Prdm16 induces the postnatal reduction in Vascular Cell Adhesion Molecule 1 (Vcam1). The postnatal disappearance of radial glia and the ending of cortical neurogenesis occur normally in Prdm16-Vcam1 double conditional knockout mice. These observations reveal novel molecular regulators of the postnatal disappearance of radial glia and the ending of embryonic neurogenesis, filling a key knowledge gap in NSC biology.

Lymphocyte deficiency alters the transcriptomes of oligodendrocytes, but not astrocytes or microglia.

Though the brain was long characterized as an immune-privileged organ, findings in recent years have shown extensive communications between the brain and peripheral immune cells. We now know that alterations in the peripheral immune system can affect the behavioral outputs of the central nervous system, but we do not know which brain cells are affected by the presence of peripheral immune cells. Glial cells including microglia, astrocytes, oligodendrocytes, and oligodendrocyte precursor cells (OPCs) are critical for the development and function of the central nervous system. In a wide range of neurological and psychiatric diseases, the glial cell state is influenced by infiltrating peripheral lymphocytes. However, it remains largely unclear whether the development of the molecular phenotypes of glial cells in the healthy brain is regulated by lymphocytes. To answer this question, we acutely purified each type of glial cell from immunodeficient Rag2-/- mice. Interestingly, we found that the transcriptomes of microglia, astrocytes, and OPCs developed normally in Rag2-/- mice without reliance on lymphocytes. In contrast, there are modest transcriptome differences between the oligodendrocytes from Rag2-/- and control mice. Furthermore, the subcellular localization of the RNA-binding protein Quaking, is altered in oligodendrocytes. These results demonstrate that the molecular attributes of glial cells develop largely without influence from lymphocytes and highlight potential interactions between lymphocytes and oligodendrocytes.

Oligodendrocyte-lineage cell exocytosis and L-type prostaglandin D synthase promote oligodendrocyte development and myelination.

In the developing central nervous system, oligodendrocyte precursor cells (OPCs) differentiate into oligodendrocytes, which form myelin around axons. Oligodendrocytes and myelin are essential for the function of the central nervous system, as evidenced by the severe neurological symptoms that arise in demyelinating diseases such as multiple sclerosis and leukodystrophy. Although many cell-intrinsic mechanisms that regulate oligodendrocyte development and myelination have been reported, it remains unclear whether interactions among oligodendrocyte-lineage cells (OPCs and oligodendrocytes) affect oligodendrocyte development and myelination. Here, we show that blocking vesicle-associated membrane protein (VAMP) 1/2/3-dependent exocytosis from oligodendrocyte-lineage cells impairs oligodendrocyte development, myelination, and motor behavior in mice. Adding oligodendrocyte-lineage cell-secreted molecules to secretion-deficient OPC cultures partially restores the morphological maturation of oligodendrocytes. Moreover, we identified L-type prostaglandin D synthase as an oligodendrocyte-lineage cell-secreted protein that promotes oligodendrocyte development and myelination in vivo. These findings reveal a novel autocrine/paracrine loop model for the regulation of oligodendrocyte and myelin development.