Enteric glia express proteolipid protein 1 and are a transcriptionally unique population of glia in the mammalian nervous system

Abstract

In the enteric nervous system (ENS), glia outnumber neurons by 4-fold and form an extensive network throughout the gastrointestinal tract. Growing evidence for the essential role of enteric glia in bowel function makes it imperative to understand better their molecular marker expression and how they relate to glia in the rest of the nervous system. We analyzed expression of markers of astrocytes and oligodendrocytes in the ENS and found, unexpectedly, that proteolipid protein 1 (PLP1) is specifically expressed by glia in adult mouse intestine. PLP1 and S100β are the markers most widely expressed by enteric glia, while glial fibrillary acidic protein (GFAP) expression is more restricted. Marker expression in addition to cellular location and morphology distinguishes a specific subpopulation of intramuscular enteric glia, suggesting that a combinatorial code of molecular markers can be used to identify distinct subtypes. To assess the similarity between enteric and extra-enteric glia, we performed RNA sequencing analysis (RNA-Seq) on PLP1-expressing cells in the mouse intestine and compared their gene expression pattern to that of other types of glia. This analysis shows that enteric glia are transcriptionally unique and distinct from other cell types in the nervous system. Enteric glia express many genes characteristic of the myelinating glia, Schwann cells and oligodendrocytes, although there is no evidence of myelination in the murine ENS.

Enteric Glia Regulate Gastrointestinal Motility but Are Not Required for Maintenance of the Epithelium in Mice

“…More than half of mucosal and submucosal glia in the ileum and colon do not express GFAP 13 . In contrast, S100β, SOX10 and PLP1 are expressed by virtually all enteric glia and the Plp1 promoter can be used to manipulate enteric glia in vivo 13 . To explore enteric glial functions, we targeted PLP1-expressing cells for elimination in mice using inducible expression of diphtheria toxin subunit A (DTA).…”

“…More recent studies have shown that enteric glia are heterogeneous and that GFAP expression is limited to a subset 12, 13 . More than half of mucosal and submucosal glia in the ileum and colon do not express GFAP 13 .…”

Postnatal development of the myenteric glial network and its modulation by butyrate

“…Using Sox10 and Ki67 as markers, we showed a progressive reduction in the number of EGC or progenitors that proliferate in the distal colonic myenteric plexus of rat pups. Although Sox10 and S100␤ expression may vary in EGC, these markers are generally coexpressed in myenteric EGC and represent the most reliable markers for these cell types (7,32). At P1, 22% Sox10 (B, F), and S100␤ (C, G) and corresponding merged photographs (D, H).…”

Toward a better understanding of enteric gliogenesis

“…7 Recent work further challenged this view and now suggests that enteric glia have a unique hybrid transcriptome profile overlapping (in order of importance) with the signature of Schwann cells, oligodendrocytes and astrocytes. 8 This apparent hybrid identity is most likely also reflective of the heterogeneity within the enteric glial cell population. For example, while most enteric glial cells co-express SOX10, PLP1 and S100b, only a subset of them also express GFAP.…”

“…For example, while most enteric glial cells co-express SOX10, PLP1 and S100b, only a subset of them also express GFAP. 8 Other work focusing on the diversity of enteric glial cells led to the identification of 4 specific types based on their morphology and their location along the serosa-to-lumen axis: star-shaped "protoplasmic gliocytes" within myenteric ganglia (type I), elongated "fibrous gliocytes" within fiber tracts (type II), mucosal and intramuscular gliocytes with 4 primary processes (type III mucosa and Type III MP/SMP , respectively) and bipolar intramuscular gliocytes (type IV). 9,10 Whether each of these subtypes has an associated physiologic role remains to be determined but differences in dye filling, calcium transient and receptor expression strongly suggest that enteric glial subtypes are functionally distinct.…”