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Abnormal CCK/CB1R axon targeting in mouse models of dystroglycanopathy

View ORCID ProfileDaniel S. Miller, View ORCID ProfileJennifer N. Jahncke, View ORCID ProfileEric Schnell, View ORCID ProfileKevin M. Wright
doi: https://doi.org/10.1101/2022.01.26.477791
Daniel S. Miller
1Neuroscience Graduate Program, Oregon Health & Science University, Portland, OR 97239, USA
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Jennifer N. Jahncke
1Neuroscience Graduate Program, Oregon Health & Science University, Portland, OR 97239, USA
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Eric Schnell
2Operative Care Division, Portland VA Health Care System
3Anesthesiology and Perioperative Medicine, Oregon Health & Science University, Portland, OR 97239, USA
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Kevin M. Wright
4Vollum Institute, Oregon Health & Science University, Portland, OR 97239, USA
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  • For correspondence: wrighke@ohsu.edu
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ABSTRACT

Dystroglycan (Dag1) is a cell adhesion molecule that links the extracellular matrix to the actin cytoskeleton, and is critical for normal muscle and brain development. Mutations in Dag1 or the genes required for its functional glycosylation result in dystroglycanopathy, which is characterized by a wide range of phenotypes including muscle weakness, brain defects, and cognitive impairments. Whereas Dystroglycan’s role in muscle and early brain development are well defined, much less is known about its role at later stages of neural circuit development including synapse formation and refinement. Recent work has found that selective deletion of Dag1 from pyramidal neurons leads to a loss of presynaptic CCK+ inhibitory neurons (INs) early in development. In this study, we investigated how IN development is affected in multiple mouse models of dystroglycanopathy. Widespread forebrain deletion of Dag1 or Pomt2, which is required for Dystroglycan glycosylation, recapitulates brain phenotypes seen in severe forms of dystroglycanopathy. CCK+ INs were present in Dag1 and Pomt2 mutant mice, but their axons failed to properly target the somatodendritic compartment of pyramidal neurons in the hippocampus. In contrast, CCK+ IN axon targeting was largely normal in mouse models of mild dystroglycanopathy with partially reduced Dystroglycan glycosylation (B4gat1, Fkrp). Furthermore, the intracellular domain of Dystroglycan appears to be dispensable for CCK+ IN axon targeting. Collectively, these data show that synaptic defects are a hallmark of severe dystroglycanopathy.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • Competing interests: The authors declare that they have no competing interests.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted January 26, 2022.
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Abnormal CCK/CB1R axon targeting in mouse models of dystroglycanopathy
Daniel S. Miller, Jennifer N. Jahncke, Eric Schnell, Kevin M. Wright
bioRxiv 2022.01.26.477791; doi: https://doi.org/10.1101/2022.01.26.477791
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Abnormal CCK/CB1R axon targeting in mouse models of dystroglycanopathy
Daniel S. Miller, Jennifer N. Jahncke, Eric Schnell, Kevin M. Wright
bioRxiv 2022.01.26.477791; doi: https://doi.org/10.1101/2022.01.26.477791

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