Transcriptomes of germinal zones of human and mouse fetal neocortex suggest a role of extracellular matrix in progenitor self-renewal

Abstract

The expansion of the neocortex during mammalian brain evolution results primarily from an increase in neural progenitor cell divisions in its two principal germinal zones during development, the ventricular zone (VZ) and the subventricular zone (SVZ). Using mRNA sequencing, we analyzed the transcriptomes of fetal human and embryonic mouse VZ, SVZ, and cortical plate. In mouse, the transcriptome of the SVZ was more similar to that of the cortical plate than that of the VZ, whereas in human the opposite was the case, with the inner and outer SVZ being highly related to each other despite their cytoarchitectonic differences. We describe sets of genes that are up-or down-regulated in each germinal zone. These data suggest that cell adhesion and cell-extracellular matrix interactions promote the proliferation and self-renewal of neural progenitors in the developing human neocortex. Notably, relevant extracellular matrix-associated genes include distinct sets of collagens, laminins, proteoglycans, and integrins, along with specific sets of growth factors and morphogens. Our data establish a basis for identifying novel cell-type markers and open up avenues to unravel the molecular basis of neocortex expansion during evolution.cerebral cortex | neural stem cells | neurogenesis N eocortex expansion is a hallmark of mammalian brain evolution. With regard to neuron number, a major cause of this expansion is the increase in the population size of neural stem and progenitor cells (NSPCs) and the number of divisions that each of the various NSPC types undergoes during cortical development (1-4). Two principal classes of these cells can be distinguished based on the location of their mitosis: (i) apical progenitors (APs), which undergo mitosis at the luminal surface of the ventricular zone (VZ); and (ii) basal progenitors (BPs), which undergo mitosis at an abventricular location, typically in the subventricular zone (SVZ) (2, 5, 6). Neurons born from AP and BP cell divisions migrate radially and settle at the basal (pial) side of the developing cortical wall to form the cortical plate (CP).Both APs and BPs comprise several types of NSPCs that differ in key cell biological features (e.g., cell polarity, cell processes, cell-to-cell junctions, nuclear migration) and in the principal modes of cell division (symmetric proliferative vs. asymmetric self-renewing vs. symmetric or asymmetric consumptive) (2, 5-10). APs comprise neuroepithelial cells, which transform into apical radial glial cells (aRGCs) at the onset of neurogenesis (11), and short neural precursors (12). BPs include basal (or outer) radial glial cells (bRGCs), transit amplifying progenitors (TAPs), and intermediate progenitor cells (IPCs) (2, 3, 13).The evolutionary expansion of the neocortex is associated with an increase in the thickness of the SVZ, which develops into two cytoarchitecturally distinct zones, an inner SVZ (ISVZ) and an outer SVZ (OSVZ) (1-4, 14, 15). The evolutionary increase in the SVZ is accompanied by a change in the proportion of BP subtypes. Fo...

From sauropsids to mammals and back: New approaches to comparative cortical development

“…However, more recent studies in ferret (Reillo and Borrell, 2012) and macaque (Betizeau et al, 2013) have shown that the cellular composition of ISVZ and OSVZ is very similar and both contain oRG and IPCs than was previously appreciated. This is also in agreement with the finding that gene expression profiles of ISVZ and OSVZ in the human developing neocortex are closely related to each other (Fietz et al, 2012; Miller et al, 2014). …”

“…In the brain, transcriptomes from the whole cerebral cortex, and developing neocortical brain compartments (ventricular zone, subventricular zone, and cortical plate, CP), exhibit different sets of transcripts. Developmental compartments have been shown to express specific gene‐signatures (Ayoub et al, 2011; Fietz et al, 2012) differing across ontogeny. Thus, a cohort of active transcripts during development and in adult cortical compartments can be differentiated at the level of gene expression, splicing, and RNA editing (Dillman et al, 2013).…”

“…At several brain developmental stages, cortical proliferative compartments have been compared between human and mouse, exhibiting a pattern of similarity between progenitor and derived postmitotic compartments (Fietz et al, 2012). This is probably associated with the radial expansion and more elaborate development of the cortical program in humans.…”

Coevolution of radial glial cells and the cerebral cortex

“…Even though any given germinal layer contains a variety of cortical progenitors and other cell types, this first approximation identified thousands of genes expressed in germinal layers at different relative levels between mouse and human. Significantly, this study also led to the intriguing finding that extracellular matrix (ECM) components are highly enriched in the OSVZ of the human fetal cortex compared with mouse (Fietz et al, 2012). Importantly, experiments performed in ferret demonstrate that signaling via ECM components, fibroblast‐ and platelet‐derived growth factors is directly involved in promoting the hyper‐proliferation and/or self‐renewal of cortical progenitors in gyrencephalic species (Fietz et al, 2010; Lui et al, 2014; Rash et al, 2013; Stenzel et al, 2014).…”

“…As a first approximation, a landmark study reported the content of the whole transcriptome of individual cortical germinal layers in both mouse and human fetuses, and compared their composition (Fietz et al, 2012). Even though any given germinal layer contains a variety of cortical progenitors and other cell types, this first approximation identified thousands of genes expressed in germinal layers at different relative levels between mouse and human.…”