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B.Y. Lee, A. Mehalow, R.S. Smith, W. Hicks, J.K. Naggert, P.M. Nishina; Prefoldin 5 (Pfdn5) Is Essential for the Development of the Mouse Photoreceptor Outer Segment (Os) . Invest. Ophthalmol. Vis. Sci. 2006;47(13):2296.
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© ARVO (1962-2015); The Authors (2016-present)
The proper development of the photoreceptor outer segment depends on faithful expression of OS molecules, their transporters, and the integrity of connecting cilium (CC). Here, we report the effects of a mutation in Prefoldin 5, a subunit of Prefoldin, a heterohexameric chaperone that transports actins and tubulins to a cytosolic containing TCP–1 (CCT) for proper folding during OS development. Actins and tubulins are crucial components of the CC.
A point mutation, T362G (L110R), in Prefoldin 5 was identified in a mutant mouse, NMF5a, generated by ENU mutagenesis. Effects of the mutation were studied using light–microscopy, ERG, and immunohistological methods.
At 4 weeks ERGs obtained from mutant mice were abnormal with a reduction in dark adapted a– and b–waves, indicating that photoreceptor cells were compromised. Severe outer retinal degeneration supported the ERG findings. Between P10.5 and P12.5, the outer nuclear layer thickness is the same in mutant and wild–type. However, the OS and IS appear thinner than those of littermate controls. Rhodopsin and rom1 are mis–localized in the outer nuclear layer and inner segment in mutants, indicating that that transport via the CC to the OS may be impaired. Close examination of the region of the OS suggests that they may not develop at all.
Our results show for the first time that a mutation within Prefoldin 5 causes abnormal outer segment development. The core cytoskeleton of the CC mainly consists of microtubules with a cluster of actin filaments at the distal part of the CC; microtubule structures are known to be crucial for the transport of OS molecules from the IS and actin filaments appear to be important of the initial morphogenesis of OS disk membranes. Therefore, it is likely that the underlying molecular cause of this abnormal OS development may be in the integrity of the CC since Prefoldin 5 is mainly involved in proper folding of tubulin and actins. However, we cannot exclude the possibility that Prefoldin 5 might interact with other molecules important for retinal function that may be impaired as a result of the identified mutation. It is also likely that the degeneration observed may be due to the abnormal accumulation of molecules in the IS and ONL that normally localized to the OS, inducing a state of cellular stress.
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