Journal article
Dystroglycan Maintains Inner Limiting Membrane Integrity to Coordinate Retinal Development
The Journal of neuroscience, Vol.37(35), pp.8559-8574
08/30/2017
DOI: 10.1523/JNEUROSCI.0946-17.2017
PMCID: PMC5577860
PMID: 28760865
Abstract
Proper neural circuit formation requires the precise regulation of neuronal migration, axon guidance, and dendritic arborization. Mutations affecting the function of the transmembrane glycoprotein dystroglycan cause a form of congenital muscular dystrophy that is frequently associated with neurodevelopmental abnormalities. Despite its importance in brain development, the role of dystroglycan in regulating retinal development remains poorly understood. Using a mouse model of dystroglycanopathy (
) and conditional
mutants of both sexes, we show that dystroglycan is critical for the proper migration, axon guidance, and dendritic stratification of neurons in the inner retina. Using genetic approaches, we show that dystroglycan functions in neuroepithelial cells as an extracellular scaffold to maintain the integrity of the retinal inner limiting membrane. Surprisingly, despite the profound disruptions in inner retinal circuit formation, spontaneous retinal activity is preserved. These results highlight the importance of dystroglycan in coordinating multiple aspects of retinal development.
The extracellular environment plays a critical role in coordinating neuronal migration and neurite outgrowth during neural circuit development. The transmembrane glycoprotein dystroglycan functions as a receptor for multiple extracellular matrix proteins and its dysfunction leads to a form of muscular dystrophy frequently associated with neurodevelopmental defects. Our results demonstrate that dystroglycan is required for maintaining the structural integrity of the inner limiting membrane (ILM) in the developing retina. In the absence of functional dystroglycan, ILM degeneration leads to defective migration, axon guidance, and mosaic spacing of neurons and a loss of multiple neuron types during retinal development. These results demonstrate that disorganization of retinal circuit development is a likely contributor to visual dysfunction in patients with dystroglycanopathy.
Details
- Title: Subtitle
- Dystroglycan Maintains Inner Limiting Membrane Integrity to Coordinate Retinal Development
- Creators
- Reena Clements - Neuroscience Graduate Program andRolf Turk - Howard Hughes Medical Institute, Department of Molecular Physiology and Biophysics, Department of Neurology, Department of Internal Medicine, The University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa 52242Kevin P Campbell - Howard Hughes Medical Institute, Department of Molecular Physiology and Biophysics, Department of Neurology, Department of Internal Medicine, The University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa 52242Kevin M Wright - Vollum Institute, Oregon Health & Science University, Portland, Oregon 97239, and
- Resource Type
- Journal article
- Publication Details
- The Journal of neuroscience, Vol.37(35), pp.8559-8574
- Publisher
- United States
- DOI
- 10.1523/JNEUROSCI.0946-17.2017
- PMID
- 28760865
- PMCID
- PMC5577860
- ISSN
- 0270-6474
- eISSN
- 1529-2401
- Grant note
- P30 NS061800 / NINDS NIH HHS R01 NS091027 / NINDS NIH HHS U54 NS053672 / NINDS NIH HHS
- Language
- English
- Date published
- 08/30/2017
- Academic Unit
- Neurology; Molecular Physiology and Biophysics; Iowa Neuroscience Institute
- Record Identifier
- 9984020851302771
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