Laminin α2 controls mouse and human stem cell behaviour during midbrain dopaminergic neuron development

Ahmed, Maqsood, Marziali, Leandro N., Arenas, Ernest, Feltri, M. Laura and ffrench-Constant, Charles ORCID: https://orcid.org/0000-0002-5621-3377 (2019) Laminin α2 controls mouse and human stem cell behaviour during midbrain dopaminergic neuron development. Development (Cambridge), 146 (16). ISSN 0950-1991

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Abstract

Development of the central nervous system requires coordination of the proliferation and differentiation of neural stem cells. Here, we show that laminin alpha 2 (lm-α2) is a component of the midbrain dopaminergic neuron (mDA) progenitor niche in the ventral midbrain (VM) and identify a concentration-dependent role for laminin α2β1γ1 (lm211) in regulating mDA progenitor proliferation and survival via a distinct set of receptors. At high concentrations, lm211-rich environments maintain mDA progenitors in a proliferative state via integrins α6β1 and α7β1, whereas low concentrations of lm211 support mDA lineage survival via dystroglycan receptors. We confirmed our findings in vivo, demonstrating that the VM was smaller in the absence of lm-α2, with increased apoptosis; furthermore, the progenitor pool was depleted through premature differentiation, resulting in fewer mDA neurons. Examination of mDA neuron subtype composition showed a reduction in later-born mDA neurons of the ventral tegmental area, which control a range of cognitive behaviours. Our results identify a novel role for laminin in neural development and provide a possible mechanism for autism-like behaviours and the brainstem hypoplasia seen in some individuals with mutations of LAMA2.

Item Type: Article
Additional Information: Funding Information: C.f.-C. is supported by a European Union FP7 Neurostemcellrepair grant (602278), a National Institutes of Health grant (5R01EB016629-04) and a Wellcome Trust Senior Investigator Award. E.A. is supported by the Vetenskapsrådet (VR 2016-01526), the Stiftelsen för strategisk forskning (SB16-0065), the European Commission (NeuroStemCellRepair), Hjärnfonden (FO2017:0059), Cancerfonden (CAN 2016/572) and SFO Strat Regen at the Karolinska Institutet (SG-2018). Deposited in PMC for release after 6 months. Funding Information: C.f.-C. is supported by a European Union FP7 Neurostemcellrepair grant (602278), a National Institutes of Health grant (5R01EB016629-04) and a Wellcome Trust Senior Investigator Award. E.A. is supported by the Vetenskapsr?det (VR 2016-01526), the Stiftelsen f?r strategisk forskning (SB16-0065), the European Commission (NeuroStemCellRepair), Hj?rnfonden (FO2017:0059), Cancerfonden (CAN 2016/572) and SFO Strat Regen at the Karolinska Institutet (SG-2018). Deposited in PMC for release after 6 months.
Uncontrolled Keywords: congenital muscular dystrophy,dopaminergic neurons,dystroglycan,extracellular matrix,integrin,laminin,neural stem cells,molecular biology,developmental biology ,/dk/atira/pure/subjectarea/asjc/1300/1312
Faculty \ School: Faculty of Medicine and Health Sciences > Norwich Medical School
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Depositing User: LivePure Connector
Date Deposited: 15 Jul 2022 14:30
Last Modified: 12 Aug 2022 05:37
URI: https://ueaeprints.uea.ac.uk/id/eprint/86227
DOI: 10.1242/dev.172668

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