Sox6 expression distinguishes dorsally and ventrally biased dopamine neurons in the substantia nigra with distinctive properties and embryonic origins

Milagros Pereira Luppi; Maite Azcorra; Giuliana Caronia-Brown; Jean Francois Poulin; Zachary Gaertner; Serafin Gatica; Oscar Andrés Moreno-Ramos; Navid Nouri; Marilyn Dubois; Yongchao C. Ma; Charu Ramakrishnan; Lief Fenno; Yoon Seok Kim; Karl Deisseroth; Francesca Cicchetti; Daniel A. Dombeck; Rajeshwar Awatramani

doi:10.1016/j.celrep.2021.109975

Sox6 expression distinguishes dorsally and ventrally biased dopamine neurons in the substantia nigra with distinctive properties and embryonic origins

Milagros Pereira Luppi, Maite Azcorra, Giuliana Caronia-Brown, Jean Francois Poulin, Zachary Gaertner, Serafin Gatica, Oscar Andrés Moreno-Ramos, Navid Nouri, Marilyn Dubois, Yongchao C. Ma, Charu Ramakrishnan, Lief Fenno, Yoon Seok Kim, Karl Deisseroth, Francesca Cicchetti, Daniel A. Dombeck^*, Rajeshwar Awatramani^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

38 Scopus citations

Abstract

Dopamine (DA) neurons in the ventral tier of the substantia nigra pars compacta (SNc) degenerate prominently in Parkinson's disease, while those in the dorsal tier are relatively spared. Defining the molecular, functional, and developmental characteristics of each SNc tier is crucial to understand their distinct susceptibility. We demonstrate that Sox6 expression distinguishes ventrally and dorsally biased DA neuron populations in the SNc. The Sox6⁺ population in the ventral SNc includes an Aldh1a1⁺ subset and is enriched in gene pathways that underpin vulnerability. Sox6⁺ neurons project to the dorsal striatum and show activity correlated with acceleration. Sox6⁻ neurons project to the medial, ventral, and caudal striatum and respond to rewards. Moreover, we show that this adult division is encoded early in development. Overall, our work demonstrates a dual origin of the SNc that results in DA neuron cohorts with distinct molecular profiles, projections, and functions.

Original language	English (US)
Article number	109975
Journal	Cell reports
Volume	37
Issue number	6
DOIs	https://doi.org/10.1016/j.celrep.2021.109975
State	Published - Nov 9 2021

Funding

We thank Michael Wegner (guinea pig anti-Sox6 antibody), Maria Grazia Spillantini (human anatomical boundaries), Vasileios Papakis (confocal imaging), and Matthew Schipma (RNA-seq analysis). This work was supported by NIH grants R01-NS119690, R01-NS096240, R01-MH110555, R21-NS092034-01A1, P50 DA044121-01A1, and 1 F31 NS122481-01A1. Experiments were conducted by M.P.L. M.A. G.C.-B. and S.G. Human analyses were performed by F.C. M.D. and J.-F.P. Sox6 mouse lines were generated by G.C.B. Intersectional viral vectors were provided by K.D. C.R. L.F. and Y.S.K. Y.C.M. provided the guinea pig anti-Lmx1a antibody. Transcriptome analysis was performed by N.N. Z.G. and O.A.M.-R. The manuscript was written by M.P.L. M.A. and R.A. The project was supervised by R.A. and D.A.D. The authors declare no competing interests. We thank Michael Wegner (guinea pig anti-Sox6 antibody), Maria Grazia Spillantini (human anatomical boundaries), Vasileios Papakis (confocal imaging), and Matthew Schipma (RNA-seq analysis). This work was supported by NIH grants R01-NS119690 , R01-NS096240 , R01-MH110555 , R21-NS092034-01A1 , P50 DA044121-01A1 , and 1 F31 NS122481-01A1 .

Keywords

Aldh1a1
Calb1
Parkinson's
Sox6
dopamine
dorsal SNc
fate map
selective vulnerability
ventral SNc

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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Pereira Luppi, M., Azcorra, M., Caronia-Brown, G., Poulin, J. F., Gaertner, Z., Gatica, S., Moreno-Ramos, O. A., Nouri, N., Dubois, M., Ma, Y. C., Ramakrishnan, C., Fenno, L., Kim, Y. S., Deisseroth, K., Cicchetti, F., Dombeck, D. A., & Awatramani, R. (2021). Sox6 expression distinguishes dorsally and ventrally biased dopamine neurons in the substantia nigra with distinctive properties and embryonic origins. Cell reports, 37(6), Article 109975. https://doi.org/10.1016/j.celrep.2021.109975

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title = "Sox6 expression distinguishes dorsally and ventrally biased dopamine neurons in the substantia nigra with distinctive properties and embryonic origins",

abstract = "Dopamine (DA) neurons in the ventral tier of the substantia nigra pars compacta (SNc) degenerate prominently in Parkinson's disease, while those in the dorsal tier are relatively spared. Defining the molecular, functional, and developmental characteristics of each SNc tier is crucial to understand their distinct susceptibility. We demonstrate that Sox6 expression distinguishes ventrally and dorsally biased DA neuron populations in the SNc. The Sox6+ population in the ventral SNc includes an Aldh1a1+ subset and is enriched in gene pathways that underpin vulnerability. Sox6+ neurons project to the dorsal striatum and show activity correlated with acceleration. Sox6− neurons project to the medial, ventral, and caudal striatum and respond to rewards. Moreover, we show that this adult division is encoded early in development. Overall, our work demonstrates a dual origin of the SNc that results in DA neuron cohorts with distinct molecular profiles, projections, and functions.",

keywords = "Aldh1a1, Calb1, Parkinson's, Sox6, dopamine, dorsal SNc, fate map, selective vulnerability, ventral SNc",

author = "{Pereira Luppi}, Milagros and Maite Azcorra and Giuliana Caronia-Brown and Poulin, {Jean Francois} and Zachary Gaertner and Serafin Gatica and Moreno-Ramos, {Oscar Andr{\'e}s} and Navid Nouri and Marilyn Dubois and Ma, {Yongchao C.} and Charu Ramakrishnan and Lief Fenno and Kim, {Yoon Seok} and Karl Deisseroth and Francesca Cicchetti and Dombeck, {Daniel A.} and Rajeshwar Awatramani",

note = "Publisher Copyright: {\textcopyright} 2021 The Author(s)",

year = "2021",

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doi = "10.1016/j.celrep.2021.109975",

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Pereira Luppi, M, Azcorra, M, Caronia-Brown, G, Poulin, JF, Gaertner, Z, Gatica, S, Moreno-Ramos, OA, Nouri, N, Dubois, M, Ma, YC, Ramakrishnan, C, Fenno, L, Kim, YS, Deisseroth, K, Cicchetti, F, Dombeck, DA & Awatramani, R 2021, 'Sox6 expression distinguishes dorsally and ventrally biased dopamine neurons in the substantia nigra with distinctive properties and embryonic origins', Cell reports, vol. 37, no. 6, 109975. https://doi.org/10.1016/j.celrep.2021.109975

TY - JOUR

T1 - Sox6 expression distinguishes dorsally and ventrally biased dopamine neurons in the substantia nigra with distinctive properties and embryonic origins

AU - Pereira Luppi, Milagros

AU - Azcorra, Maite

AU - Caronia-Brown, Giuliana

AU - Poulin, Jean Francois

AU - Gaertner, Zachary

AU - Gatica, Serafin

AU - Moreno-Ramos, Oscar Andrés

AU - Nouri, Navid

AU - Dubois, Marilyn

AU - Ma, Yongchao C.

AU - Ramakrishnan, Charu

AU - Fenno, Lief

AU - Kim, Yoon Seok

AU - Deisseroth, Karl

AU - Cicchetti, Francesca

AU - Dombeck, Daniel A.

AU - Awatramani, Rajeshwar

PY - 2021/11/9

Y1 - 2021/11/9

N2 - Dopamine (DA) neurons in the ventral tier of the substantia nigra pars compacta (SNc) degenerate prominently in Parkinson's disease, while those in the dorsal tier are relatively spared. Defining the molecular, functional, and developmental characteristics of each SNc tier is crucial to understand their distinct susceptibility. We demonstrate that Sox6 expression distinguishes ventrally and dorsally biased DA neuron populations in the SNc. The Sox6+ population in the ventral SNc includes an Aldh1a1+ subset and is enriched in gene pathways that underpin vulnerability. Sox6+ neurons project to the dorsal striatum and show activity correlated with acceleration. Sox6− neurons project to the medial, ventral, and caudal striatum and respond to rewards. Moreover, we show that this adult division is encoded early in development. Overall, our work demonstrates a dual origin of the SNc that results in DA neuron cohorts with distinct molecular profiles, projections, and functions.

AB - Dopamine (DA) neurons in the ventral tier of the substantia nigra pars compacta (SNc) degenerate prominently in Parkinson's disease, while those in the dorsal tier are relatively spared. Defining the molecular, functional, and developmental characteristics of each SNc tier is crucial to understand their distinct susceptibility. We demonstrate that Sox6 expression distinguishes ventrally and dorsally biased DA neuron populations in the SNc. The Sox6+ population in the ventral SNc includes an Aldh1a1+ subset and is enriched in gene pathways that underpin vulnerability. Sox6+ neurons project to the dorsal striatum and show activity correlated with acceleration. Sox6− neurons project to the medial, ventral, and caudal striatum and respond to rewards. Moreover, we show that this adult division is encoded early in development. Overall, our work demonstrates a dual origin of the SNc that results in DA neuron cohorts with distinct molecular profiles, projections, and functions.

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KW - Calb1

KW - Parkinson's

KW - Sox6

KW - dopamine

KW - dorsal SNc

KW - fate map

KW - selective vulnerability

KW - ventral SNc

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DO - 10.1016/j.celrep.2021.109975

M3 - Article

C2 - 34758317

AN - SCOPUS:85118856032

SN - 2211-1247

VL - 37

JO - Cell reports

JF - Cell reports

IS - 6

M1 - 109975

ER -

Sox6 expression distinguishes dorsally and ventrally biased dopamine neurons in the substantia nigra with distinctive properties and embryonic origins

Abstract

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Keywords

ASJC Scopus subject areas

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