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Quantitative trait locus mapping identifies Col4a6 as a novel regulator of striatal dopamine level and axonal branching in mice

Mélanie H. Thomas, Yujuan Gui, Pierre Garcia, Mona Karout, Christian Jaeger, Zdenka Hodak, Alessandro Michelucci, Heike Kollmus, Arthur Centeno, Klaus Schughart, Rudi Balling, Michel Mittelbronn, Joseph H. Nadeau, Robert W. Williams, Thomas Sauter, Lasse Sinkkonen, View ORCID ProfileManuel Buttini
doi: https://doi.org/10.1101/2020.06.28.176206
Mélanie H. Thomas
1Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Belvaux, Luxembourg
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Yujuan Gui
2Department of Life Sciences and Medicine (DLSM), University of Luxembourg, Belvaux, Luxembourg
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Pierre Garcia
1Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Belvaux, Luxembourg
3National Center of Pathology (NCP), Laboratoire National de Santé (LNS), Dudelange, Luxembourg
4Luxembourg Centre of Neuropathology (LCNP), Luxembourg
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Mona Karout
1Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Belvaux, Luxembourg
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Christian Jaeger
1Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Belvaux, Luxembourg
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Zdenka Hodak
1Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Belvaux, Luxembourg
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Alessandro Michelucci
1Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Belvaux, Luxembourg
5Neuro-Immunology Group, Department of Oncology (DONC), Luxembourg Institute of Health (LIH), Luxembourg, Luxembourg
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Heike Kollmus
6Department of Infection Genetics, Helmholtz Centre for Infection Research, Braunschweig, Germany
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Arthur Centeno
7Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, USA
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Klaus Schughart
6Department of Infection Genetics, Helmholtz Centre for Infection Research, Braunschweig, Germany
8University of Veterinary Medicine Hannover, Hannover, Germany
9Department of Microbiology, Immunology and Biochemistry, University of Tennessee Health Science Center, Memphis, Tennessee, USA
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Rudi Balling
1Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Belvaux, Luxembourg
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Michel Mittelbronn
1Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Belvaux, Luxembourg
3National Center of Pathology (NCP), Laboratoire National de Santé (LNS), Dudelange, Luxembourg
4Luxembourg Centre of Neuropathology (LCNP), Luxembourg
5Neuro-Immunology Group, Department of Oncology (DONC), Luxembourg Institute of Health (LIH), Luxembourg, Luxembourg
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Joseph H. Nadeau
10Pacific Northwest Research Institute, Seattle, Washington, United States
11Maine Medical Center Research Institute, Scarborough, Maine USA
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Robert W. Williams
7Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, USA
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Thomas Sauter
2Department of Life Sciences and Medicine (DLSM), University of Luxembourg, Belvaux, Luxembourg
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Lasse Sinkkonen
2Department of Life Sciences and Medicine (DLSM), University of Luxembourg, Belvaux, Luxembourg
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  • For correspondence: lasse.sinkkonen@uni.lu manuel.buttini@uni.lu
Manuel Buttini
1Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Belvaux, Luxembourg
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  • ORCID record for Manuel Buttini
  • For correspondence: lasse.sinkkonen@uni.lu manuel.buttini@uni.lu
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Abstract

The features of dopaminergic neurons (DAns) of nigrostriatal circuitry are orchestrated by a multitude of yet unknown factors, many of them genetic. Genetic variation between individuals at baseline can lead to differential susceptibility to and severity of diseases. As decline of DAns, a characteristic of Parkinson’s disease, heralds a significant decrease in dopamine level, measuring dopamine can reflect the integrity of DAns. To identify novel genetic regulators of the integrity of DAns, we used the Collaborative Cross (CC) mouse strains as model system to search for quantitative trait loci (QTLs) related to dopamine levels in the dorsal striatum. The dopamine levels in dorsal striatum varied greatly in the eight CC founder strains, and the differences were inheritable in 32 derived CC strains. QTL mapping in these CC strains identified a QTL associated with dopamine level on chromosome X containing 393 genes. RNA-seq analysis of the ventral midbrain of two of the founder strains with large striatal dopamine difference (C57BL/6J and A/J) revealed 24 differentially expressed genes within the QTL. The protein-coding gene with the highest expression difference was Col4a6, which exhibited a 9-fold reduction in A/J compared to C57BL/6J, consistent with decreased dopamine levels in A/J. Publicly available single cell RNA-seq data from developing human midbrain suggests that Col4a6 is highly expressed in radial glia-like cells and neuronal progenitors, indicating possible involvement in neurogenesis. Interestingly, the lowered dopamine levels were accompanied by reduced striatal axonal branching of striatal DAns in A/J compared to C57BL/6J. Because Col4a6 is known to control axogenesis in non-mammal model organisms, we hypothesize that different dopamine levels in mouse dorsal striatum are due to differences in axogenesis induced by varying COL4A6 levels during neural development.

Competing Interest Statement

The authors have declared no competing interest.

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Quantitative trait locus mapping identifies Col4a6 as a novel regulator of striatal dopamine level and axonal branching in mice
Mélanie H. Thomas, Yujuan Gui, Pierre Garcia, Mona Karout, Christian Jaeger, Zdenka Hodak, Alessandro Michelucci, Heike Kollmus, Arthur Centeno, Klaus Schughart, Rudi Balling, Michel Mittelbronn, Joseph H. Nadeau, Robert W. Williams, Thomas Sauter, Lasse Sinkkonen, Manuel Buttini
bioRxiv 2020.06.28.176206; doi: https://doi.org/10.1101/2020.06.28.176206
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Quantitative trait locus mapping identifies Col4a6 as a novel regulator of striatal dopamine level and axonal branching in mice
Mélanie H. Thomas, Yujuan Gui, Pierre Garcia, Mona Karout, Christian Jaeger, Zdenka Hodak, Alessandro Michelucci, Heike Kollmus, Arthur Centeno, Klaus Schughart, Rudi Balling, Michel Mittelbronn, Joseph H. Nadeau, Robert W. Williams, Thomas Sauter, Lasse Sinkkonen, Manuel Buttini
bioRxiv 2020.06.28.176206; doi: https://doi.org/10.1101/2020.06.28.176206

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