Graded Arrays of Spinal and Supraspinal V2a Interneuron Subtypes Underlie Forelimb and Hindlimb Motor Control

Abstract

The spinal cord contains neural networks that enable regionally distinct motor outputs along the body axis. Nevertheless, it remains unclear how segment-specific motor computations are processed because the cardinal interneuron classes that control motor neurons appear uniform at each level of the spinal cord. V2a interneurons are essential to both forelimb and hindlimb movements, and here we identify two major types that emerge during development: type I neurons marked by high Chx10 form recurrent networks with neighboring spinal neurons and type II neurons that downregulate Chx10 and project to supraspinal structures. Types I and II V2a interneurons are arrayed in counter-gradients, and this network activates different patterns of motor output at cervical and lumbar levels. Single-cell RNA sequencing (RNA-seq) revealed type I and II V2a neurons are each comprised of multiple subtypes. Our findings uncover a molecular and anatomical organization of V2a interneurons reminiscent of the orderly way motor neurons are divided into columns and pools.

Single cell transcriptomics reveals spatial and temporal dynamics of gene expression in the developing mouse spinal cord

“…Neurons differentiate asynchronously from progenitors by undergoing a series of transcriptional changes that converts a proliferative progenitor into specific classes of neurons. Post-mitotic neurons subsequently further diversify into discrete subsets of physiologically distinct neuronal subtypes and commence formation of the circuitry characteristic of the spinal cord Borowska et al, 2013;Goulding, 2009;Hayashi et al, 2018;Kiehn, 2016;Lu et al, 2015). Following the period of neurogenesis, which lasts until ~e13 in mouse, the remaining undifferentiated progenitors in the neural tube produce glia cells.…”

Large scale analysis of the diversity and complexity of the adult spinal cord neurotransmitter typology

“…To evaluate our findings and the extent of neurotransmitter co-expression and dynamics, we performed a proof-of-concept analysis focusing on one of the most well-characterized spinal interneuron populations, the V2a interneurons (Arber, 2012;Goulding, 2009;Kiehn, 2016;2011). V2a interneurons are one of the most important excitatory neuronal classes for the operation of the vertebrate locomotor network (Al-Mosawie et al, 2007;Crone et al, 2008;Dougherty and Kiehn, 2010;Hayashi et al, 2018;Joshi et al, 2009;Lundfald et al, 2007;Zhong et al, 2011), as demonstrated by studies on zebrafish (Ampatzis et al, 2014;Ausborn et al, 2012;Eklöf-Ljunggren et al, 2012;Kimura et al, 2006;McLean et al, 2008;McLean and Fetcho 2009;Menelaou et al, 2014;Song et al, 2018). In keeping with previous reports (Ampatzis et al, 2014), we detected 23.59 ± 0.503 V2a interneurons (n = 22 zebrafish; Figure S4B) per hemisegment in the adult zebrafish spinal cord.…”

Molecular Logic of Spinocerebellar Tract Neuron Diversity and Connectivity

“…We found that SCTN subtypes can be defined by Recent studies suggest that molecular programs acting along the rostrocaudal axis play key roles in establishing subtype-specific features of spinal interneuron classes. Both V1 and V2a interneuron classes are generated from a single progenitor domain, but give rise to dozens of molecularly distinct subtypes, which can be defined through differences in settling position, connectivity, and transcription factor gene expression 21,22,31,32 . While studies of V1 interneurons have demonstrated an important role of Hox genes in patterning transcription factor expression 21 , the identities of their subtype-specific targets are unclear.…”

“…Hox genes are expressed by multiple neuronal populations within the hindbrain and spinal cord, suggesting a broader role neuronal specification. Although recent studies have implicated Hox function during the differentiation of interneurons in the ventral spinal cord 21,22 , the identity of their downstream target effectors and potential roles in sensorymotor circuit assembly have not been investigated.…”