Cells transitioning along this axis progressively lose their initially strong neurogenic bias and adopt gene expression profiles characteristic of canonical glial and immune functions. These experiments lead us to suggest a previously unknown configuration of ENS lineage differentiation trajectories which proposes that, in contrast to a widely assumed bifurcation model, neurogenic trajectories branch off a progenitor-to-glia differentiation axis. Here we characterize at single-cell resolution the gene expression and chromatin accessibility profile of mammalian ENS progenitors and their descendants at key developmental stages and adulthood. Despite these studies, it is unclear how the differentiation processes of the ENS, unfolding over protracted periods of prenatal and postnatal development, enable mature EGCs to perform their canonical neuroregulatory roles and immune functions in the tissue environment of the adult gut and simultaneously serve as facultative neural progenitors. Although in mammals enteric neurogenesis is completed shortly after birth, we and other groups have presented evidence that enteric glial cells (EGCs) from postnatal (including adult) rodents can differentiate into neurons in gut injury models and in culture 11, 12, 13, 14. An ideal scenario for restoring ENS function in these conditions would entail the reactivation of developmental programs capable of inducing heterochronic differentiation of resident neural crest-derived cells into appropriate neuronal and glial cell types. Relatively common conditions, such as intestinal inflammation or aging can also lead to severe gastrointestinal malfunction due to loss of enteric neurons 9, 10. The critical roles of the ENS in survival and health are highlighted by developmental deficits, such as Hirschsprung’s disease (congenital megacolon), which results from a localised but life-threatening absence of neurons and glia from the distal colon 8. Most enteric neurons and glia originate from a small population of autonomic neural crest cells (ANCCs) which invade the foregut during embryogenesis and, following highly coordinated programs of self-renewal and differentiation, generate integrated networks of diverse neuronal and glial cell types throughout the gut 6, 7. The enteric nervous system (ENS) encompasses the gut-intrinsic neuroglial networks that regulate vital gastrointestinal functions, including motility, epithelial secretion and immunity 4, 5. How glial cell lineages acquire mature characteristics while retaining properties of undifferentiated neuronal progenitors, is unclear. For example, populations of mature glial cells undergoing constitutive neurogenesis have been identified in specific locations of the peripheral nervous system, such as the carotid body of rodents and the intestine of zebrafish 2, 3. However, glial cells often share molecular markers with neural stem cells and have the capacity to differentiate into neurons under certain conditions 1. Neurogenesis and gliogenesis are commonly formalized as alternative and irreversible cell fate decisions made by bipotential progenitors. Our work provides mechanistic insight into the regulatory landscape underpinning the development of intestinal neural circuits and generates a platform for advancing glial cells as therapeutic agents for the treatment of neural deficits. Molecular profiling and gene targeting of enteric glial cells in a cell culture model of enteric neurogenesis and a gut injury model demonstrate that neuronal differentiation of glia is driven by transcriptional programs employed in vivo by early progenitors. ![]() ![]() Key neurogenic loci in early enteric nervous system progenitors remain in open chromatin configuration in mature enteric glia, thus facilitating neuronal differentiation under appropriate conditions. ![]() Using single cell transcriptomic profiling, we show that enteric glial cells represent a cell state attained by autonomic neural crest cells as they transition along a linear differentiation trajectory that allows them to retain neurogenic potential while acquiring mature glial functions. ![]() Glial cells have been proposed as a source of neural progenitors, but the mechanisms underpinning the neurogenic potential of adult glia are not known.
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