Remotely Produced and Axon-Derived Netrin-1 Instructs GABAergic Neuron Migration and Dopaminergic Substantia Nigra Development

Brignani, Sara; Raj, Divya; Schmidt, Ewoud R.E.; Dudukcu, O.; Adolfs, Youri; Ruiter, A.A. De; Rybiczka-Tesulov, Mateja; Verhagen, Marieke G.; Meer, Christiaan van der; Broekhoven, Mark H.; Moreno-Bravo, Juan Antonio; Grossouw, Laurens M.; Dumontier, Émilie; Cloutier, Jean-François; Chédotal, Alain; Pasterkamp, R. Jeroen

doi:10.1016/j.neuron.2020.05.037

Cited by 33 publications

(32 citation statements)

References 80 publications

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“…Labeling of Bcl11a-expressing mDA neurons was scarcer in the SN compared to the VTA (Figure 4C,D; Supplemental Figure 5C,D), consistent with a lower percentage of Bcl11a-expressing mDA neurons in the SN than in the VTA (Figure 1; Figure 5). The sparse labeling allowed us to visualize patches of innervation likely derived from single SN axons (Brignani et al, 2020). These patches were restricted to the DMS and ventral TS, consistent with the findings obtained with the embryonically-induced intersectional labeling of Bcl11a-expressing neurons (Figure 3, Figure 4E,F; Supplemental Figure 5E,F).…”

Section: Bcl11a-expressing Mda Neurons Form a Subcircuit In The Dopamsupporting

confidence: 83%

The transcription factor BCL11A defines a distinctive subset of dopamine neurons in the developing and adult midbrain

Tolve

Ulusoy

Islam

et al. 2020

Preprint

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Midbrain dopaminergic (mDA) neurons are diverse in their projection targets, impact on behavior and susceptibility to neurodegeneration. Little is known about the molecular mechanisms that establish this diversity in mDA neurons during development. We find that the transcription factor Bcl11a defines a subset of mDA neurons in the developing and adult murine brain. By combining intersectional labeling and viral-mediated tracing we show that Bcl11a-expressing mDA neurons form a highly specific subcircuit within the dopaminergic system. We demonstrate that Bcl11a-expressing mDA neurons in the substantia nigra (SN) are particularly vulnerable to neurodegeneration in an α-synuclein overexpression model of Parkinson’s disease. Inactivation of Bcl11a in developing mDA neurons results in anatomical changes, deficits in motor learning and a dramatic increase in the susceptibility to α-synuclein-induced degeneration in SN-mDA neurons. In summary, we identify an mDA subpopulation with highly distinctive characteristics defined by the expression of the transcription factor Bcl11a already during development.

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Section: Bcl11a-expressing Mda Neurons Form a Subcircuit In The Dopamsupporting

confidence: 83%

The transcription factor BCL11A defines a distinctive subset of dopamine neurons in the developing and adult midbrain

Tolve

Ulusoy

Islam

et al. 2020

Preprint

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“…The NTN1 presence in the mesodiencephalic dopaminergic neurons has been recently demonstrated in adult brains, and we have proved it during development (Dominici et al, 2017;Jasmin et al, 2020). Nevertheless, other authors have also described the NTN1 production by dopaminergic neurons of the developing SNc and VTA (Livesey and Hunt, 1997;Li et al, 2014;Brignani et al, 2020). Furthermore, in the Netrin1bGal hypomorph (Serafini et al, 1996), the mutant allele generates a fusion protein between NTN1 and BGAL.…”

Section: Ntn1-dcc Mechanism Has a Complex Role In The Guidance Of Mhbsupporting

confidence: 67%

“…Once we demonstrated its role, we identified Ntn1 as the main attractive molecule. This secreted molecule is expressed in the SNc and VTA ( Livesey and Hunt, 1997 ; Li et al, 2014 ; Brignani et al, 2020 ). In our work, we have demonstrated that Ntn1 is responsible for the correct guidance of the mHb axons toward their final target and that SNc and VTA are intermediate targets in their navigation.…”

Section: Introductionmentioning

confidence: 99%

Netrin 1-Mediated Role of the Substantia Nigra Pars Compacta and Ventral Tegmental Area in the Guidance of the Medial Habenular Axons

Andreu-Cervera

Madrigal

Andrés

et al. 2021

Front. Cell Dev. Biol.

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The fasciculus retroflexus is an important fascicle that mediates reward-related behaviors and is associated with different psychiatric diseases. It is the main habenular efference and constitutes a link between forebrain regions, the midbrain, and the rostral hindbrain. The proper functional organization of habenular circuitry requires complex molecular programs to control the wiring of the habenula during development. However, the mechanisms guiding the habenular axons toward their targets remain mostly unknown. Here, we demonstrate the role of the mesodiencephalic dopaminergic neurons (substantia nigra pars compacta and ventral tegmental area) as an intermediate target for the correct medial habenular axons navigation along the anteroposterior axis. These neuronal populations are distributed along the anteroposterior trajectory of these axons in the mesodiencephalic basal plate. Using in vitro and in vivo experiments, we determined that this navigation is the result of netrin 1 attraction generated by the mesodiencephalic dopaminergic neurons. This attraction is mediated by the receptor deleted in colorectal cancer (DCC), which is strongly expressed in the medial habenular axons. The increment in our knowledge on the fasciculus retroflexus trajectory guidance mechanisms opens the possibility of analyzing if its alteration in mental health patients could account for some of their symptoms.

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“…In developing cerebral cortex, Netrin-1 mRNA is highly expressed in VZ/SVZ ( Zhang et al, 2018 ). It is of interest to note the report by Brignani et al (2020) that Netrin-1, produced in the forebrain and provided to the midbrain through axon projections, instructs the migration of GABAergic neurons into the ventral SN, which supports the expression of Netrin-1 in developing neurons in forebrain ( Brignani et al, 2020 ). In line with these reports are observations by Allen's in situ and single-cell RNA-seq databases on the websites.…”

Section: Discussionmentioning

confidence: 85%

Myosin X Interaction with KIF13B, a Crucial Pathway for Netrin-1-Induced Axonal Development

Peng

Zhao

et al. 2020

J. Neurosci.

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Myosin X (Myo X) transports cargos to the tips of filopodia for cell adhesion, migration, and neuronal axon guidance. Deleted in Colorectal Cancer (DCC) is one of Myo X cargos essential for Netrin-1-regulated axon pathfinding. Myo X's function in axon development in vivo and the underlying mechanisms remain elusive. Here, we provide evidence for Myo X's role in Netrin-1-DCC regulated axon development in developing mouse neocortex. Knocking-out (KO) or knocking-down (KD) Myo X in cortical neurons of embryonic mouse brain impairs axon initiation and contralateral branching/targeting. Similar axon deficits are detected in Netrin-1-KO or DCC-KD cortical neurons. Further proteomic analysis of Myo X binding proteins identifies KIF13B (a kinesin family motor protein). Myo X interaction with KIF13B is induced by Netrin-1. Netrin-1 promotes anterograde transportation of Myo X into axons in KIF13B dependent manner. KIF13B-KD cortical neurons exhibit similar axon deficits. Together, these results reveal Myo X-KIF13B as a critical pathway for Netrin-1 promoted axon initiation and branching/targeting. SIGNIFICANCE STATEMENT Netrin-1 increases Myo X interaction with KIF13B, and thus promotes axonal delivery of Myo X and axon initiation and contralateral branching in developing cerebral neurons, revealing unrecognized functions and mechanisms underlying Netrin-1 regulation of axon development.

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Remotely Produced and Axon-Derived Netrin-1 Instructs GABAergic Neuron Migration and Dopaminergic Substantia Nigra Development

Cited by 33 publications

References 80 publications

The transcription factor BCL11A defines a distinctive subset of dopamine neurons in the developing and adult midbrain

The transcription factor BCL11A defines a distinctive subset of dopamine neurons in the developing and adult midbrain

Netrin 1-Mediated Role of the Substantia Nigra Pars Compacta and Ventral Tegmental Area in the Guidance of the Medial Habenular Axons

Myosin X Interaction with KIF13B, a Crucial Pathway for Netrin-1-Induced Axonal Development

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