Developmental trajectories of thalamic progenitors revealed by single-cell transcriptome profiling and Shh perturbation

Kiya W Govek; Sixing Chen; Paraskevi Sgourdou; Yao Yao; Steven Woodhouse; Tingfang Chen; Marc V Fuccillo; Douglas J Epstein; Pablo G Camara

doi:10.1016/j.celrep.2022.111768

Developmental trajectories of thalamic progenitors revealed by single-cell transcriptome profiling and Shh perturbation

Cell Rep. 2022 Dec 6;41(10):111768. doi: 10.1016/j.celrep.2022.111768.

Authors

Kiya W Govek¹, Sixing Chen², Paraskevi Sgourdou², Yao Yao³, Steven Woodhouse¹, Tingfang Chen², Marc V Fuccillo⁴, Douglas J Epstein⁵, Pablo G Camara⁶

Affiliations

¹ Department of Genetics, Perelman School of Medicine, University of Pennsylvania, 3700 Hamilton Walk, Philadelphia, PA 19104, USA; Institute for Biomedical Informatics, Perelman School of Medicine, University of Pennsylvania, 3700 Hamilton Walk, Philadelphia, PA 19104, USA.
² Department of Genetics, Perelman School of Medicine, University of Pennsylvania, 3700 Hamilton Walk, Philadelphia, PA 19104, USA.
³ Department of Animal and Dairy Science, Regenerative Bioscience Center, University of Georgia, 425 River Road, Athens, GA 30602, USA.
⁴ Department of Neuroscience, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
⁵ Department of Genetics, Perelman School of Medicine, University of Pennsylvania, 3700 Hamilton Walk, Philadelphia, PA 19104, USA. Electronic address: epsteind@pennmedicine.upenn.edu.
⁶ Department of Genetics, Perelman School of Medicine, University of Pennsylvania, 3700 Hamilton Walk, Philadelphia, PA 19104, USA; Institute for Biomedical Informatics, Perelman School of Medicine, University of Pennsylvania, 3700 Hamilton Walk, Philadelphia, PA 19104, USA. Electronic address: pcamara@pennmedicine.upenn.edu.

Abstract

The thalamus is the principal information hub of the vertebrate brain, with essential roles in sensory and motor information processing, attention, and memory. The complex array of thalamic nuclei develops from a restricted pool of neural progenitors. We apply longitudinal single-cell RNA sequencing and regional abrogation of Sonic hedgehog (Shh) to map the developmental trajectories of thalamic progenitors, intermediate progenitors, and post-mitotic neurons as they coalesce into distinct thalamic nuclei. These data reveal that the complex architecture of the thalamus is established early during embryonic brain development through the coordinated action of four cell differentiation lineages derived from Shh-dependent and -independent progenitors. We systematically characterize the gene expression programs that define these thalamic lineages across time and demonstrate how their disruption upon Shh depletion causes pronounced locomotor impairment resembling infantile Parkinson's disease. These results reveal key principles of thalamic development and provide mechanistic insights into neurodevelopmental disorders resulting from thalamic dysfunction.

Keywords: CP: Neuroscience; Sonic hedgehog; brain development; diencephalon; enhancers; infantile Parkinson’s disease; locomotor activity; single-cell RNA-seq; thalamus.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Thalamus* / cytology

Grants and funding

R01 NS039421/NS/NINDS NIH HHS/United States