General and cell-type-specific aspects of the motor neuron maturation transcriptional program

Abstract

Building a nervous system is a protracted process that starts with the specification of individual neuron types and ends with the formation of mature neural circuits. The molecular mechanisms that regulate the temporal progression of maturation in individual cell types remain poorly understood. In this work, we have mapped the gene expression and chromatin accessibility changes in mouse spinal motor neurons throughout their lifetimes. We found that both motor neuron gene expression and putative regulatory elements are dynamic during the first three weeks of postnatal life, when motor circuits are maturing. Genes that are up-regulated during this time contribute to adult motor neuron diversity and function. Almost all of the chromatin regions that gain accessibility during maturation are motor neuron specific, yet a majority of the transcription factor binding motifs enriched in these regions are shared with other mature neurons. Collectively, these findings suggest that a core transcriptional program operates in a context-dependent manner to access cell-type-specific cis-regulatory systems associated with maturation genes. Discovery of general principles governing neuronal maturation might inform methods for transcriptional reprogramming of neuronal age and for improved modeling of age-related neurodegenerative diseases.

Single-cell transcriptomic analysis unveils spinal motor neuron subtype diversity underpinning the water-to-land transition in vertebrates

“…In this study, we describe the molecular codes for 26 LMC subclusters (16 and 10 for brachial and lumbar LMC MNs, respectively) that display unique combinatorial neuropeptide and TF expression profiles. Our findings support the terminal selector hypothesis that combinations of Hox/Lim homeodomain TFs might elicit a battery of subtype-specific genes, including ligands and receptors, cell adhesion molecules, and neurotransmitter-related genes, which would serve as regulators to robustly govern the fate and functions of subtypes [94][95][96] .…”

“…Second, some neuronal identities may only be elicited after spinal cord wiring is complete at the postnatal stage. Accordingly, an examination of spinal MN identity at later time-points may prove enlightening 95 . Although we determined the number of subclusters using a robust ensemble approach based on spectral graph theory in mathematics, the inherent noisy and sparse nature of single-cell transcriptomics bring additional challenges to the estimation of optimal number of clusters in the data.…”

Loss of mouse Stmn2 function causes motor neuropathy

“…Interestingly, Stmn2 intensity per micron 2 showed a modest but significant positive correlation to soma size (R 2 = 0.089, p < 0.001), potentially suggesting selectivity for higher Stmn2 expression in motor neuron subtypes known to be most susceptible to degeneration in ALS (Figures S5B-S5D). To gain better insight into the expression of Stmn2 within specific subpopulations of a skeletal motor neurons, we costained WT P21 lumbar mouse spinal cords with a recently described adult a motor neuron marker, Spp1, that encodes for the extracellular matrix protein, Osteopontin, and Stmn2 (Blum et al, 2021;Fischer et al, 2004;Frey et al, 2000;Morisaki et al, 2016;Patel et al, 2021;Pun et al, 2006). We found Stmn2 to be expressed specifically in a subset of Spp1+ neurons, suggesting a selective expression of Stmn2 in a specific subset of presumptive a motor neurons (Figure S5E).…”

MiR-138-5p upregulation during neuronal maturation parallels with an increase in neuronal survival

“…Various factors cause these changes, such as environment [Piatti et al, 2011;Tooley et al, 2021], growth factors (e.g. NGF) [Crutcher, 1986;Landreth, 1999;Aloe et al, 2015], and transcriptome [He and Yu, 2018;Patel et al, 2021].…”

“…Various factors cause these changes, such as environment [Piatti et al ., 2011; Tooley et al ., 2021], growth factors (e.g. NGF) [Crutcher, 1986; Landreth, 1999; Aloe et al ., 2015], and transcriptome [He and Yu, 2018; Patel et al ., 2021]. Modulation of transcriptome by non-coding RNA includes microRNAs, small RNA molecules of about 19-25 nucleotides capable of controlling the expression of hundreds of genes and regulating the state and fate of cells [Kosik, 2010].…”