PhD student City University of Hong Kong HONGKONG, Hong Kong
Abstract: The dorsal root ganglion (DRG), derived from neural crest cells, is composed of sensory neurons and satellite glia, and plays a crucial role in transmitting various sensations such as touch, pain, itch, temperature, and spatial positioning Abnormal DRG development leads to congenital sensory neuropathies, which are frequently with metabolic syndromes, suggesting the potential role of metabolic control in regulating DRG development. Despite this, the interplay between metabolic regulation and the gene regulatory network during DRG development remains poorly understood.
To address this, we established human dorsal root ganglion organoids(DRGOs)that recaptured developmental reprograms as observed in vivo, showing the emergence of bipotent progenitors, neuronal-glial lineage segregation, and maturation into various sensory neurons subtypes. Building on SnRNA-seq analysis of human embryonic DRGs and biosensors validation in human DRG organoids, we found that both sensory and glial progenitors exhibit high ATP production and NAD+/NADH ratios, which were maintained in differentiated satellite glia. As sensory neurons matured, there was a metabolic shift from oxidative phosphorylation to glycolysis. Notably, we identified MMD2, a key regulator of mitochondrial oxidative energy metabolism, as a key regulator in this metabolic transition. MMD2 expression is primarily found in early differentiating sensory neuron progenitors and glial lineages. Functional analysis reveals that reduced MMD2 expression severely impairs sensory neuronal differentiation and axonal outgrowth, while overexpression of MMD2 promotes sensory neuronal differentiation with increased axonal density. Additionally, inhibition of glycolysis by 2-DG significantly reduces the population of mature sensory neurons and shortens axon lengths, further implicating glycolytic regulation in promoting sensory neuron maturation.
These results provide new insights into the dynamic metabolic programs that contribute to different stages of sensory neurogenesis and gliogenesis, and MMD2 could function as a key regulator in mediating this metabolic switching. These results enhance our understanding of the etiology of sensory neurocristopathies and pave the way for energy/metabolic-based therapies for these disorders.
