Document Detail

Retinal degeneration and failure of photoreceptor outer segment formation in mice with targeted deletion of the Joubert syndrome gene, Ahi1.
MedLine Citation:
PMID:  20592197     Owner:  NLM     Status:  MEDLINE    
Vertebrate photoreceptors have a modified cilium composed of a basal body, axoneme and outer segment. The outer segment includes stacked membrane discs, containing opsin and the signal transduction apparatus mediating phototransduction. In photoreceptors, two distinct classes of vesicles are trafficked. Synaptic vesicles are transported down the axon to the synapse, whereas opsin-containing vesicles are transported to the outer segment. The continuous replacement of the outer segments imposes a significant biosynthetic and trafficking burden on the photoreceptors. Here, we show that Ahi1, a gene that when mutated results in the neurodevelopmental disorder, Joubert syndrome (JBTS), is required for photoreceptor sensory cilia formation and the development of photoreceptor outer segments. In mice with a targeted deletion of Ahi1, photoreceptors undergo early degeneration. Whereas synaptic proteins are correctly trafficked, photoreceptor outer segment proteins fail to be transported appropriately or are significantly reduced in their expression levels (i.e., transducin and Rom1) in Ahi1(-/-) mice. We show that vesicular targeting defects in Ahi1(-/-) mice are cilium specific, and our evidence suggests that the defects are caused by a decrease in expression of the small GTPase Rab8a, a protein required for accurate polarized vesicular trafficking. Thus, our results suggest that Ahi1 plays a role in stabilizing the outer segment proteins, transducin and Rom1, and that Ahi1 is an important component of Rab8a-mediated vesicular trafficking in photoreceptors. The retinal degeneration observed in Ahi1(-/-) mice recapitulates aspects of the retinal phenotype observed in patients with JBTS and suggests the importance of Ahi1 in photoreceptor function.
Jennifer E Westfall; Carlton Hoyt; Qin Liu; Yi-Chun Hsiao; Eric A Pierce; Patrick S Page-McCaw; Russell J Ferland
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  The Journal of neuroscience : the official journal of the Society for Neuroscience     Volume:  30     ISSN:  1529-2401     ISO Abbreviation:  J. Neurosci.     Publication Date:  2010 Jun 
Date Detail:
Created Date:  2010-07-01     Completed Date:  2010-07-22     Revised Date:  2014-09-15    
Medline Journal Info:
Nlm Unique ID:  8102140     Medline TA:  J Neurosci     Country:  United States    
Other Details:
Languages:  eng     Pagination:  8759-68     Citation Subset:  IM    
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MeSH Terms
Brain Diseases
Cilia / metabolism
Eye Proteins / metabolism
GTP-Binding Protein alpha Subunits / metabolism
Gene Deletion
Membrane Proteins / metabolism
Mice, Inbred BALB C
Mice, Knockout
Proto-Oncogene Proteins / genetics,  metabolism*
Retina / metabolism
Retinal Degeneration / metabolism*
Retinal Photoreceptor Cell Outer Segment / metabolism*
Synaptic Vesicles / metabolism
Transducin / metabolism
rab GTP-Binding Proteins / metabolism
Grant Support
EY12910/EY/NEI NIH HHS; K01 MH071801/MH/NIMH NIH HHS; K01 MH071801-06/MH/NIMH NIH HHS; MH71801/MH/NIMH NIH HHS; R01 EY012910/EY/NEI NIH HHS; R01 EY012910-12/EY/NEI NIH HHS
Reg. No./Substance:
0/Ahi1 protein, mouse; 0/Eye Proteins; 0/GTP-Binding Protein alpha Subunits; 0/Gnat1 protein, mouse; 0/Membrane Proteins; 0/Proto-Oncogene Proteins; 0/Rab8a protein, mouse; 0/Rom1 protein, mouse; EC 3.6.1.-/Transducin; EC 3.6.1.-/rab GTP-Binding Proteins

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