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S.M. Culican, A.J. Bloom, M. Morgan, R.O. L. Wong, A. DiAntonio; Eye Specific Projections to the dLGN Segregate Normally but Are Ectopically Located in the PHR Mutant Mouse . Invest. Ophthalmol. Vis. Sci. 2006;47(13):5380.
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© ARVO (1962-2015); The Authors (2016-present)
To understand what role PHR, a potential regulator of synaptic morphology, plays in the specification of retino–geniculate projections in mammals.
Methods and Rationale: :
PHR is the mouse homolog to highwire in drosophila, and RPM1 in c. elegans, which play a role in regulation of synaptic morphology. While its function is still under much investigation, evidence suggests that it acts at least in part as a ubiquitin ligase. To examine the role of PHR in mammals, we generated both constitutive and conditional PHR knock out mice. Constituative loss of PHR results in lethality at birth and many morphologic defects throughout the CNS and PNS. In normal mice, PHR is expressed at high levels in the ganglion cells of the retina (RGCs). To examine the function of PHR in the developing visual system, we generated a conditional knock–out of PHR using the Cre/loxP system. Animals that were homozygous for the floxed allele of PHR were crossed with alphaPax/Cre resulting in offspring with loss of PHR only in the eye (cPHRko). We examined retinal morphology, physiological activity and projection patterns these mice. Retinal activity was studied with multi–electrode array recordings. Because the phenotype in the invertebrate species is synaptic, we examined the dorsal lateral geniculate nucleus (dLGN), where RGCs synapse in the CNS, by bulk labeling of the RGC axons with fluorescent cholera toxin.
The cPHRko animals exhibited normal behavior and were viable and fertile. Gross anatomic examination of the retinas revealed normal morphology. Multi–electrode array recordings of mutant retinas at P10 demonstrated normal retinal wave activity. Axon projection patterns in the dLGN were studied in adult animals and at different developmental ages. This analysis demonstrated that developmental segregation of left and right eye inputs to the dLGN does occur, resulting in non–overlapping inputs in adulthood. Quantitative analysis of the segregation of these projections indicates that as early as P10 there is no difference in the degree of overlap of left and right eye inputs between the PHR mutants and littermate controls. Anatomically, the ipsilateral projection was confined to a discrete region within the dLGN. The location of this projection, however, was ventro–lateral and oriented orthogonally to the region normally occupied by the ipsilateral axons.
These data suggest that PHR plays a role in topographic specificity that is independent of activity dependent segregation.
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