Abstract
Neurogenesis in the developing neocortex begins with the generation of the preplate, which consists of early-born neurons including Cajal-Retzius (CR) cells and subplate neurons. Here, utilizing the Ebf2-EGFP transgenic mouse in which EGFP initially labels the preplate neurons then persists in CR cells, we reveal the dynamic transcriptome profiles of early neurogenesis and CR cell differentiation. Genome-wide RNA-seq and ChIP-seq analyses at multiple early neurogenic stages have revealed the temporal gene expression dynamics of early neurogenesis and distinct histone modification patterns in early differentiating neurons. We have identified a new set of coding genes and lncRNAs involved in early neuronal differentiation and validated with functional assays in vitro and in vivo. In addition, at E15.5 when Ebf2-EGFP+ cells are mostly CR neurons, single-cell sequencing analysis of purified Ebf2-EGFP+ cells uncovers molecular heterogeneities in CR neurons, but without apparent clustering of cells with distinct regional origins. Along a pseudotemporal trajectory these cells are classified into three different developing states, revealing genetic cascades from early generic neuronal differentiation to late fate specification during the establishment of CR neuron identity and function. Our findings shed light on the molecular mechanisms governing the early differentiation steps during cortical development, especially CR neuron differentiation.
Highlights
The mammalian cortical neurogenesis occurs on a precise time schedule during development
Early-born neurons including CajalRetzius (CR) cells and subplate neurons form the preplate in the developing cerebral cortex, CR neurons occupy the layer 1, playing an important role in cortical histogenesis
We revealed CR neuron signatures and cell type-specific histone modification patterns along early neuron specification
Summary
The mammalian cortical neurogenesis occurs on a precise time schedule during development. Subplate neurons contribute to the guidance of corticofugal and thalamocortical axons during early development and are important for the functional maturation and plasticity of the cortical circuitry [9,10]. Discovered more than a century ago by Retzius and Ramon y Cajal, CR neurons have been studied extensively [4,11]. Best known for their expression of Reln, CR neurons regulate the inside-out migration of cortical neurons, correct layer formation, maintenance of RGC and cortical patterning [12]. Recent studies have identified the genes enriched in subplate neurons by microarray and RNA-seq analysis [15,16,17], providing a comprehensive gene expression profile of the subplate at different developmental stages, which offers valuable insights on molecular mechanisms
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