Molecular and functional definition of the developing human striatum

Abstract

The complexity of the human brain derives from the intricate interplay of molecular instructions during development. Here we systematically investigated gene expression changes in the prenatal human striatum and cerebral cortex during development from post-conception weeks 2 to 20. We identified tissue-specific gene coexpression networks, differentially expressed genes and a minimal set of bimodal genes, including those encoding transcription factors, that distinguished striatal from neocortical identities. Unexpected differences from mouse striatal development were discovered. We monitored 36 determinants at the protein level, revealing regional domains of expression and their refinement, during striatal development. We electrophysiologically profiled human striatal neurons differentiated in vitro and determined their refined molecular and functional properties. These results provide a resource and opportunity to gain global understanding of how transcriptional and functional processes converge to specify human striatal and neocortical neurons during development.

Zika Virus Disrupts Phospho-TBK1 Localization and Mitosis in Human Neuroepithelial Stem Cells and Radial Glia

“…NCX-NES cells expressed FOXG1 and OTX2 (Figure 1E and Figure S1D), key transcription factors demarcating proliferative zones of the early human forebrain (Onorati et al, 2014). On the other hand, SC-NES cells were positive for the caudal regional marker HOXB4 (Krumlauf et al, 1993) (Figure S1L), thus demonstrating maintenance of regional identity even after more than 10 passages.…”

Reversal of Phenotypic Abnormalities by CRISPR/Cas9-Mediated Gene Correction in Huntington Disease Patient-Derived Induced Pluripotent Stem Cells

“…Forebrain NPCs were subsequently differentiated into GABAergic neurons expressing mature neuronal marker MAP2, neurotransmitter gamma-aminobutyric acid (GABA), and presynaptic marker synaptophysin (SYP) on day 48 (Figure 3E). The transcription factor NKX2.1, a marker of the human medial and lateral ganglionic eminence regions, which represent the predominant developmental origin of striatal tissue (Maroof et al., 2013, Onorati et al., 2014), was also highly elevated at 34 and 48 days of neuronal differentiation (Figure 3F). Consistent with previous reports (HD iPSC Consortium, 2012), no mutant HTT-containing aggregates were detected in neurons differentiated from HD hiPSCs (Figure S3).…”

Developmental alterations in Huntington's disease neural cells and pharmacological rescue in cells and mice

“…Finally, we compared HD DEGs to genes that change in expression during human striatal maturation 26 . Genes implicated in development of human striatum are regulators of genes differentially expressed in our HD neural cells (Supplementary Fig.…”

“…Neuronal and neurodevelopmental pathways are altered in differentiated HD neural cells, including those regulated by Wnt and NEUROD1, and affect expression of related genes, such as ASCL1 ( Mash1 ), GAD1 and POU4F2 . Levels of PSD2 and GAD1 , which are among the most downregulated genes in differentiated HD lines, are essential for development of human striatum 26 .…”