Molecular diversity and migration of GABAergic neurons in the developing ventral midbrain

Özge Düdükcü; Divya D.A. Raj; Lieke L. van de Haar; Laurens M. Grossouw; Louisa E. Linders; Oxana Garritsen; Youri Adolfs; Nicky C.H. van Kronenburg; Mark H. Broekhoven; Troy H.W. Kapteijns; Frank J. Meye; R. Jeroen Pasterkamp

doi:10.1016/j.isci.2024.111239

Molecular diversity and migration of GABAergic neurons in the developing ventral midbrain

Özge Düdükcü, Divya D.A. Raj, Lieke L. van de Haar, Laurens M. Grossouw, Louisa E. Linders, Oxana Garritsen, Youri Adolfs, Nicky C.H. van Kronenburg, Mark H. Broekhoven, Troy H.W. Kapteijns, Frank J. Meye, R. Jeroen Pasterkamp^*

^*Corresponding author for this work

Neurology

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1 Scopus citations

Abstract

Dopaminergic neurons in the ventral midbrain (mDA) are surrounded by GABAergic neurons. The full extent of GABAergic neuron subtypes occupying this region and the mechanisms that underlie their development and function are largely unknown. Therefore, we performed single-cell RNA sequencing (scRNA-seq) of fluorescence-activated cell sorting (FACS)-isolated GABAergic neurons in the developing mouse ventral midbrain. Several distinct GABAergic neuron subtypes were identified based on transcriptomic profiles and spatially assigned to the ventral midbrain using in situ hybridization and immunohistochemistry for specific markers. A subset of GABAergic clusters that co-expressed mDA markers was studied in more detail and showed distinctive molecular, functional, and wiring properties. Finally, migration of different GABAergic neuron subtypes required netrin-1 from different cellular sources acting via distinct receptor mechanisms. Overall, our work provides insight into the heterogeneity and spatial organization of GABAergic neurons in the developing ventral midbrain and begins to dissect the mechanisms that underlie their development.

Original language	English (US)
Article number	111239
Journal	iScience
Volume	27
Issue number	11
DOIs	https://doi.org/10.1016/j.isci.2024.111239
State	Published - Nov 15 2024

Funding

We thank Christiaan van der Meer and Anna de Ruiter for technical assistance; Robert Burgess, Lisa Goodrich, Anton Berns, Marten Smidt, Mario Capecchi, Alain Chedotal, Jean-Francois Cloutier, Alessandra Pierani, and Corette Wierenga for mouse lines and tissues; Rudolf Jaenisch for PCAGS-FLPe-puro; and Juha Partanen for cDNAs for ISH probes. This research was supported by the Netherlands Organisation for Scientific Research ( ALW-VICI 865.14.004 ) and Stichting ParkinsonFonds (to R.J.P.). Partially supported by NWO Gravitation program BRAINSCAPES: Roadmap from Neurogenetics to Neurobiology ( NWO: 024.004.012 ) (to R.J.P.).

Keywords

Cellular neuroscience
Developmental neuroscience
Molecular neuroscience

ASJC Scopus subject areas

General

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10.1016/j.isci.2024.111239

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Düdükcü, Ö., Raj, D. D. A., van de Haar, L. L., Grossouw, L. M., Linders, L. E., Garritsen, O., Adolfs, Y., van Kronenburg, N. C. H., Broekhoven, M. H., Kapteijns, T. H. W., Meye, F. J., & Pasterkamp, R. J. (2024). Molecular diversity and migration of GABAergic neurons in the developing ventral midbrain. iScience, 27(11), Article 111239. https://doi.org/10.1016/j.isci.2024.111239

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abstract = "Dopaminergic neurons in the ventral midbrain (mDA) are surrounded by GABAergic neurons. The full extent of GABAergic neuron subtypes occupying this region and the mechanisms that underlie their development and function are largely unknown. Therefore, we performed single-cell RNA sequencing (scRNA-seq) of fluorescence-activated cell sorting (FACS)-isolated GABAergic neurons in the developing mouse ventral midbrain. Several distinct GABAergic neuron subtypes were identified based on transcriptomic profiles and spatially assigned to the ventral midbrain using in situ hybridization and immunohistochemistry for specific markers. A subset of GABAergic clusters that co-expressed mDA markers was studied in more detail and showed distinctive molecular, functional, and wiring properties. Finally, migration of different GABAergic neuron subtypes required netrin-1 from different cellular sources acting via distinct receptor mechanisms. Overall, our work provides insight into the heterogeneity and spatial organization of GABAergic neurons in the developing ventral midbrain and begins to dissect the mechanisms that underlie their development.",

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AU - Garritsen, Oxana

AU - Adolfs, Youri

AU - van Kronenburg, Nicky C.H.

AU - Broekhoven, Mark H.

AU - Kapteijns, Troy H.W.

AU - Meye, Frank J.

AU - Pasterkamp, R. Jeroen

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Molecular diversity and migration of GABAergic neurons in the developing ventral midbrain

Abstract

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