Transcription factor expression defines subclasses of developing projection neurons highly similar to single-cell RNA-seq subtypes

Abstract

We are only just beginning to catalog the vast diversity of cell types in the cerebral cortex. Such categorization is a first step toward understanding how diversification relates to function. All cortical projection neurons arise from a uniform pool of progenitor cells that lines the ventricles of the forebrain. It is still unclear how these progenitor cells generate the more than 50 unique types of mature cortical projection neurons defined by their distinct gene-expression profiles. Moreover, exactly how and when neurons diversify their function during development is unknown. Here we relate gene expression and chromatin accessibility of two subclasses of projection neurons with divergent morphological and functional features as they develop in the mouse brain between embryonic day 13 and postnatal day 5 in order to identify transcriptional networks that diversify neuron cell fate. We compare these gene-expression profiles with published profiles of single cells isolated from similar populations and establish that layer-defined cell classes encompass cell subtypes and developmental trajectories identified using single-cell sequencing. Given the depth of our sequencing, we identify groups of transcription factors with particularly dense subclass-specific regulation and subclass-enriched transcription factor binding motifs. We also describe transcription factor-adjacent long noncoding RNAs that define each subclass and validate the function of Myt1l in balancing the ratio of the two subclasses in vitro. Our multidimensional approach supports an evolving model of progressive restriction of cell fate competence through inherited transcriptional identities.

Forebrain Neural Precursor Cells Are Differentially Vulnerable to Zika Virus Infection

“…In contrast to longstanding assumptions, recent data indicate that the aRGC population is heterogeneous and can undergo temporal transcriptomic change during the neurogenesis period (Tyler et al, 2015, Heavner et al, 2020, Miyata et al, 2004, Ugomma et al, 2020. In ZIKV infected tissue, we found that a proportion of aRGC fibers were perturbed while others appeared to develop normally.…”

“…Emerging data on differences between progenitor cell groups might be crucial in elucidating nuanced mechanisms of ZIKV infection and consequent changes in neuronal output. NPCs can be categorized into sub-classes by transcriptional profile, morphology, and location within the ventricular zone (VZ) and subventricular zone (SVZ) (Figure 1A) (Tyler et al, 2015, Tamamaki et al, 2001, Hartfuss et al, 2001, Gal et al, 2006, Rakic, 1972, Hodge et al, 2019, Englund et al, 2005, Tasic et al, 2018, Heavner et al, 2020, Haubensak et al, 2004, Miyata et al, 2004, Noctor et al, 2004, Li et al, 2020, Holsapple et al, 2003. Recent advancements in single cell RNA sequencing (scRNAseq) provide the opportunity to study the heterogeneity of NPCs and their daughter cells at new levels of resolution.…”

SATB2‐LEMD2 interaction links nuclear shape plasticity to regulation of cognition‐related genes

“…In addition, a large cohort of transcription factors with established roles in cortex development was also identified as dysregulated in Lemd2 knockdown cultures. We observed a significant overlap (hypergeometric P-value = 0.0009, Fischer's exact test, OR = 1.8) between the genes deregulated in LEMD2-depleted Bic-stimulated neurons and the genes encoding deep or upper layer projection neuron-specific transcription factors (Heavner et al, 2020). To examine whether LEMD2 and SATB2 exert similar effects on gene expression in cortical neurons, we compared LEMD2-and SATB2-dependent transcriptome changes under identical culture conditions.…”

The Epigenome in Neurodevelopmental Disorders

“…In addition to neurogenesis, DNA methylation and DNMT function are also implicated in the regulation of neuronal migration, which is suggested to lead to different NDDs when being disrupted ( Figure 1 and Supplementary Table S1 ; Copp and Harding, 1999 ; Gleeson, 2001 ; Pilz et al, 2002 ; Heavner et al, 2020 ). Migratory deficits of projection neurons and inhibitory interneurons are suspected to cause numerous neuropsychiatric defects, such as ASD, Tourette syndrome, epileptic seizures, or SZ, which form an own category of neuronal migration disorders (NMDs) ( Figures 1 , 2 and Supplementary Table S1 ; Copp and Harding, 1999 ; Pilz et al, 2002 ; Guarnieri et al, 2018 ).…”