Defining developmental diversification of diencephalon neurons through single cell gene expression profiling

Abstract

The embryonic diencephalon forms integration centers and relay stations in the forebrain. Anecdotal expression studies suggest that the diencephalon contains multiple developmental compartments and subdivisions. Here, we utilized single cell RNA sequencing to profile transcriptomes of dissociated cells from the diencephalon of E12.5 mouse embryos. We identified the divergence of different progenitors, intermediate progenitors, and emerging neurons. By mapping the identified cell groups to their spatial origins, we characterized the molecular features of cell types and cell states arising from various diencephalic domains. Furthermore, we reconstructed the developmental trajectory of distinct cell lineages, and thereby identified the genetic cascades and gene regulatory networks underlying the progression of the cell cycle, neurogenesis and cellular diversification. The analysis provides new insights into the molecular mechanisms underlying the amplification of intermediate progenitor cells in the thalamus. The single cell-resolved trajectories not only confirm a close relationship between the rostral thalamus and prethalamus, but also uncover an unexpected close relationship between the caudal thalamus, epithalamus and rostral pretectum. Our data provide a useful resource for systematic studies of cell heterogeneity and differentiation kinetics within the diencephalon.

Astrocytes and neurons share region-specific transcriptional signatures that confer regional identity to neuronal reprogramming

“…While these scenarios are not mutually exclusive, the latter may provide an attractive mechanism by which neurons could modulate the spatial distribution of astrocytes ( 13 ). Our clonal analyses reveal that neurons and sibling astrocytes originating from the same thalamic progenitor clone populate very similar territories, respecting boundaries among thalamic nuclei, extending earlier observations of the existence of nucleus-specific progenitor domains in the thalamus ( 26 , 27 , 36 ). Recent single-cell spatial transcriptomic mapping has revealed that in the cortex, astrocytes exhibit heterogeneity that does not follow neuronal layering ( 13 ).…”

Cre Recombinase Driver Mice Reveal Lineage-Dependent and -Independent Expression of Brs3 in the Mouse Brain

“…4 A , Extended Data Fig. 4-1 ) ( Guo Q, Li JYH, 2019 ; Huang KW, Sabatini BL, 2020 ; Huang et al, 2019 ; Huisman et al, 2019 ; Mizrak et al, 2020 ; Tepe et al, 2018 ; Van Hove et al, 2019 ; Wizeman et al, 2019 ). Generally, the Brs3 scRNA expression/nonexpression pattern matched that in the BRS3-Cre mice.…”

“… Datasets with fewer Brs3 -positive cells are listed. See studies by Saunders et al (2018) , Tepe et al (2018) , Guo and Li (2019) , Huang et al, 2019 ), Huisman et al (2019) , Van Hove et al (2019) , Wizeman et al (2019) , Huang and Sabatini (2020) , and Mizrak et al (2020) . Download .…”

TCF7L2 regulates postmitotic differentiation programs and excitability patterns in the thalamus

“…The habenula controls reward- and aversion-driven behaviours by connecting cortical and subcortical regions with the monoamine system in the brainstem ( Benekareddy et al, 2018 ; Hikosaka, 2010 ). During postmitotic differentiation, thalamic and habenular neurons segregate into discrete nuclei ( Shi et al, 2017 ; Wong et al, 2018 ), develop a variety of subregional identities ( Guo and Li, 2019 ; Nakagawa, 2019 ; Phillips et al, 2019 ), extend axons toward their targets ( Hikosaka et al, 2008 ; López-Bendito, 2018 ) and acquire electrophysiological characteristics postnatally ( Yuge et al, 2011 ). The knowledge of the mechanisms that control postmitotic development in this region is important, because its functional dysconnectivity, which possibly originates from the period of postmitotic maturation, is implicated in schizophrenia, autism and other mental disorders ( Browne et al, 2018 ; Steullet, 2019 ; Whiting et al, 2018 ; Woodward et al, 2017 ).…”