A comprehensive transcriptional map of primate brain development

Abstract

The transcriptional underpinnings of brain development remain poorly understood, particularly in humans and closely related non-human primates. We describe a high resolution transcriptional atlas of rhesus monkey brain development that combines dense temporal sampling of prenatal and postnatal periods with fine anatomical parcellation of cortical and subcortical regions associated with human neuropsychiatric disease. Gene expression changes more rapidly before birth, both in progenitor cells and maturing neurons, and cortical layers and areas acquire adult-like molecular profiles surprisingly late postnatally. Disparate cell populations exhibit distinct developmental timing but also unexpected synchrony of processes underlying neural circuit construction including cell projection and adhesion. Candidate risk genes for neurodevelopmental disorders including primary microcephaly, autism spectrum disorder, intellectual disability, and schizophrenia show disease-specific spatiotemporal enrichment within developing neocortex. Human developmental expression trajectories are more similar to monkey than rodent, and approximately 9% of genes show human-specific regulation with evidence for prolonged maturation or neoteny.

Single-Cell Profiling of an In Vitro Model of Human Interneuron Development Reveals Temporal Dynamics of Cell Type Production and Maturation

“…Between D100 and D125 in vitro, the rate of transcriptomic changes appeared to slow. A slow-down in gene expression dynamics has been observed in previous studies of human cortical development (Bakken et al, 2016;Colantuoni et al, 2011). It is possible that our in vitro observations reflect similar changes occurring at equivalent ages in vivo, or that some extrinsic element necessary for continued development of these cells is missing from our protocol, as previous work has suggested that development is comparatively slow in vitro (Sadegh and Macklis, 2014).…”

“…more mature) pseudotime neurons ( Figure 3B, right panels). To verify these results, we compared gene expression changes correlated with pseudotime for our in vitro cells to gene expression patterns observed in the developing non-human primate and human brains ( Figure S6) (Bakken et al, 2016). We find that genes positively or negatively correlated with pseudotime in vitro are expressed in similar patterns in vivo.…”

Single-cell gene expression analysis reveals regulators of distinct cell subpopulations among developing human neurons

“…To date, many studies have shown the heterogeneity of neural precursor cells (Johnson et al 2015;Llorens-Bobadilla et al 2015) and neurons (Molyneaux et al 2007;Pollen et al 2014;Darmanis et al 2015;Usoskin et al 2015) in mouse and human brain by scRNA-seq. However, due to complexity of data analysis of cellular dynamics, coupled with the biological variability (birth, death, and differentiation) of individual cells, as well as the presence of technical, environmental, and intracellular noise (Kuznetsov 2001(Kuznetsov , 2003Kuznetsov et al 2002;Kim and Marioni 2013;Kharchenko et al 2014;Buettner et al 2015;Daigle et al 2015;Vu et al 2016), it remains a challenge to interpret the heterogeneity and dynamics of NPC to neuron transitions (Camp et al 2015;Bakken et al 2016;Yao et al 2017). Given the lack of synchronous development, the molecular patterns that switch on and switch off pathways governing alternative neuronal fate choices (Ming and Song 2011) are not clear.…”

Regional scattering of primate subplate

“…3 H]dT in macaque monkeys at various gestational ages to label the cohorts of neurons that were born at that period to establish the inside-first, outside-last generation of cortical layers in primates and produce fundamental insights into the timing of the generation of the macaque cortical neuronal cohorts that we still use today (7). Since then we gained a much better understanding of the subplate and its dynamic interactions with incoming afferents and forming cortical circuits in a variety of species (4, [8][9][10][11].…”

“…Since then we gained a much better understanding of the subplate and its dynamic interactions with incoming afferents and forming cortical circuits in a variety of species (4, [8][9][10][11]. Additionally, the subplate has been the subject of imaging studies and transcriptomic analyses because of increasing evidence for its association with various cognitive developmental disorders (7,(12)(13)(14).…”