Heterogeneous fates of simultaneously-born neurons in the cortical ventricular zone

Abstract

Neocortical excitatory neurons belong to diverse cell types, which can be distinguished by their dates of birth, laminar location, connectivity, and molecular identities. During embryogenesis, apical progenitors (APs) located in the ventricular zone first give birth to deep-layer neurons, and next to superficial-layer neurons. While the overall sequential construction of neocortical layers is well-established, whether APs produce multiple neuron types at single time points of corticogenesis is unknown. To address this question, here we used FlashTag to fate-map simultaneously-born (i.e. isochronic) cohorts of AP daughter neurons at successive stages of corticogenesis. We reveal that early in corticogenesis, isochronic neurons differentiate into heterogeneous laminar, hodological and molecular cell types. Later on, instead, simultaneously-born neurons have more homogeneous fates. Using single-cell gene expression analyses, we identify an early postmitotic surge in the molecular heterogeneity of nascent neurons during which some early-born neurons initiate and partially execute late-born neuron transcriptional programs. Together, these findings suggest that as corticogenesis unfolds, mechanisms allowing increased homogeneity in neuronal output are progressively implemented, resulting in progressively more predictable neuronal identities.

A critical period of translational control during brain development at codon resolution

“…In more evolutionarily ancient systems like that of Caenorhabditis elegans, and to an extent in the mammalian spinal cord, combinatorial expression of Homeobox cluster transcription factors sharply demarcates distinct neuronal populations 58,59 . In the mammalian neocortex, a transcription factor code accounting for the immense cellular diversity has been elusive, and neural stem cells and differentiated neurons harbor a pool of mRNAs inclusive of diverse neuronal fates 4,5,[7][8][9] . We propose that a broad transcriptome 60 is filtered at the protein level for tightly timed, rapidly scalable and spatially targeted gene expression to assemble highly evolved neuronal circuits.…”

“…7 Institute of Neuroanatomy, Charité-Universitätsmedizin Berlin, Berlin, Germany. 8 Institute of Biology, Humboldt University of Berlin, Berlin, Germany. 9 Institute of Medical Physics and Biophysics, Charité-Universitätsmedizin Berlin, Berlin, Germany.…”

“…Cellular transitions are uniquely complex during prenatal brain development, when neural stem cells deploy highly sophisticated gene expression programs for neuronal specification 2,3 . In evolutionarily advanced brain regions like the neocortex, a cell's transcriptional signature alone appears insufficient to account for the enormous cellular diversity, and single-cell RNA sequencing (scRNA-seq) analyses support this idea [4][5][6][7][8][9] . Although transcriptomes define broad classes of neurons, a striking conclusion from recent studies is the degree of homogeneity in mRNA pools between distinct neuronal lineages during prenatal differentiation 4,8 , in postnatal circuits 7 , and even between neurons and astrocytes 10 .…”

“…In evolutionarily advanced brain regions like the neocortex, a cell's transcriptional signature alone appears insufficient to account for the enormous cellular diversity, and single-cell RNA sequencing (scRNA-seq) analyses support this idea [4][5][6][7][8][9] . Although transcriptomes define broad classes of neurons, a striking conclusion from recent studies is the degree of homogeneity in mRNA pools between distinct neuronal lineages during prenatal differentiation 4,8 , in postnatal circuits 7 , and even between neurons and astrocytes 10 . Considering whether neuronal differentiation in the neocortex uses a more 'generic' transcriptome 4 has led researchers in the field to ask recently whether neuronal identity is a stochastic rather than deterministic Article https://doi.org/10.1038/s41594-022-00882-9 gene expression overall is quite stable between E12.5 and E14, a burst of regulation occurs at E15.5 at both transcriptional and translational levels, with a significant effect on the proteome.…”

Foxp1 acts upstream of Vegfa, suppresses cortical angiogenesis, and promotes hypoxia in radial glia

“…The temporal specification of neuronal subtypes in the mammalian cortex arises through progressive changes in the transcriptional states of cortical progenitors termed radial glia (RG) (Desai and McConnell, 2000; Shen et al, 2006; Telley et al, 2019). As neurogenesis proceeds, RG potential becomes more restricted and increasingly influenced by extrinsic factors and substrates (Desai and McConnell, 2000; Heavner et al, 2020; Magrinelli et al, 2022; Shen et al ., 2006; Telley et al ., 2019). RG line the ventricular zone (VZ), proliferate and self-renew to maintain a progenitor population.…”