Activity-dependent expression of Fezf2 regulates inhibitory synapse formation
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE247075 | GEO | 2026/09/14
REPOSITORIES: GEO
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Project description:Cortical projection neurons comprise classes of neurons connecting the cerebral cortex to distant targets in the nervous system. Each projection neuron class acquires a distinct molecular identity and develops characteristic patterns of axonal projection and dendritic arborization that determine their inputs, outputs, and distinct functions. How different aspects of neuron identity, including axonal and dendritic morphology, are coordinated appropriately in each specific neuron type is not known. A network of transcription factors, including the selector gene Fezf2, is central to specifying cortical projection neuron fates. However, regulation down-stream of these fate-determinant transcription factors to control different aspects of neuron identity is not understood, particularly as it relates to the development of distinct dendritic arbors that determine the inputs to each projection neuron class. Here we show that the miR-193b~365 microRNA cluster downstream of Fezf2 cooperatively represses the signaling molecule Mapk8 to regulate dendritic development in a neuron subtype-specific manner.
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Project description:Layer 5 extratelencephalic (ET) neurons are a main class of neocortical projection neurons that predominate in the motor cortex and send their axon to multiple proximal and distal targets including the thalamus, pons, medulla and spinal cord1-6. Precise connectivity of ET neurons is critical for fine motor control; they are central to loss of function upon spinal cord injury and specifically degenerate in amyotrophic lateral sclerosis7-10. ET neurons consist of several subtypes of cells with distinct laminar and areal locations, molecular identities, connectivities, and functions11,12. Two cardinal subtypes of ET neurons have been identified: neurons that express Nprs1 or Hpgd and project proximally to the pons and thalamus (ETprox), and neurons that express Slco2a1 and project more distally to the pons, medulla and spinal cord (ETdist)11. Despite their critical function, how these neuronal subtypes emerge during development and acquire their area-specific distributions remains unaddressed. Here, using combinations of anatomical labeling, MAPseq mapping13, and single- nucleus transcriptomics across developing cortical areas, we reveal that these two subtypes of ET neurons are present at birth along opposite antero-posterior cortical gradients. We first characterize area-specific developmental axonal dynamics of ETprox and ETdist neurons and find that the former can emerge by pruning of subsets of ETdist neurons. We next identify area- and ET neuron subtype-specific developmental transcriptional programs to identify key target genes in vivo and predict their gene regulatory networks. Finally, we reprogram ET neuron subtype- specific connectivity from motor to visual-like, by generating more proximal connections through postnatal in vivo knockdown of three subtype-specific transcription factors. Together, these findings delineate the functional transcriptional programs controlling ET neuron diversity across cortical areas and provide a molecular blueprint to investigate and direct the developmental emergence of corticospinal motor function.
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