Cone Photoreceptor Degeneration and Neuroinflammation in the Zebrafish Bardet-Biedl Syndrome 2 (bbs2) Mutant Does Not Lead to Retinal Regeneration

Abstract

Bardet-Biedl syndrome (BBS) is a heterogeneous and pleiotropic autosomal recessive disorder characterized by obesity, retinal degeneration, polydactyly, renal dysfunction, and mental retardation. BBS results from defects in primary and sensory cilia. Mutations in 21 genes have been linked to BBS and proteins encoded by 8 of these genes form a multiprotein complex termed the BBSome. Mutations in BBS2, a component of the BBSome, result in BBS as well as non-syndromic retinal degeneration in humans and rod degeneration in mice, but the role of BBS2 in cone photoreceptor survival is not clear. We used zebrafish bbs2–/– mutants to better understand how loss of bbs2 leads to photoreceptor degeneration. Zebrafish bbs2–/– mutants exhibited impaired visual function as larvae and adult zebrafish underwent progressive cone photoreceptor degeneration. Cone degeneration was accompanied by increased numbers of activated microglia, indicating an inflammatory response. Zebrafish exhibit a robust ability to regenerate lost photoreceptors following retinal damage, yet cone degeneration and inflammation was insufficient to trigger robust Müller cell proliferation. In contrast, high intensity light damage stimulated Müller cell proliferation and photoreceptor regeneration in both wild-type and bbs2–/– mutants, although the bbs2–/– mutants could only restore cones to pre-damaged densities. In summary, these findings suggest that cone degeneration leads to an inflammatory response in the retina and that BBS2 is necessary for cone survival. The zebrafish bbs2 mutant also represents an ideal model to identify mechanisms that will enhance retinal regeneration in degenerating diseases.

The Bardet-Biedl protein Bbs1 controls photoreceptor outer segment protein and lipid composition

“…Their observations led to the hypothesis that PR OSs act as a "sink for membrane proteins", whereby the high membrane content of OSs makes them a default destination for membrane proteins, with the BBSome responsible for removing those proteins that should not reside in the OSs (reviewed by Seo & Datta 39 ). In support of this hypothesis, accumulation of the IS protein syntaxin3 in the OS of Bbs8 -/mice and bbs2 -/zebrafish was recently described 40,41 .…”

“…To further investigate the role of the BBSome in photoreceptor function, we turned to the zebrafish, an established animal model for ciliopathies [42][43][44] . The cone-rich retina of zebrafish larvae represents a particular asset to study this photoreceptor subtype compared to the rod-dominated mouse retina, as diverging effects on cone and rod photoreceptors have been described 38,41,45 . In this work, we generated a new zebrafish bbs1 knock-out model and found that despite normal retinal development and photoreceptor differentiation, visual functional deficits were present prior to the appearance of any morphological anomaly in mutant fish.…”

“…However, we observed the development of a spinal curvature in mutant adult fish. Scoliosis is a commonly observed phenotype in zebrafish ciliopathy mutants 41,46 . Given the lack of significant phenotypes in zgbbs1 -/larvae, and since maternal contribution of transcript or protein in the egg can rescue early developmental defects in zebrafish, we next generated maternal zygotic bbs1 homozygous mutants (mzbbs1 -/-) by crossing zgbbs1 -/females with heterozygous or homozygous mutant males.…”

Retinal Stem Cell ‘Retirement Plans’: Growth, Regulation and Species Adaptations in the Retinal Ciliary Marginal Zone

“…However, very few studies have examined the activation or proliferative changes occurring in genetic degenerative models of similar human diseases. In one zebrafish study modelling Bardet-Biedl syndrome (BBS), a condition resulting in retinal degeneration due to defects in the photoreceptor outer segments, it was shown that little regenerative response was initiated from Müller cells following cone photoreceptor loss, despite displaying inflammatory responses [ 139 ]. Furthermore, high-intensity light damage could stimulate Müller glia-mediated photoreceptor regeneration in these mutants but only to pre-light injury levels [ 139 ].…”

“…In one zebrafish study modelling Bardet-Biedl syndrome (BBS), a condition resulting in retinal degeneration due to defects in the photoreceptor outer segments, it was shown that little regenerative response was initiated from Müller cells following cone photoreceptor loss, despite displaying inflammatory responses [ 139 ]. Furthermore, high-intensity light damage could stimulate Müller glia-mediated photoreceptor regeneration in these mutants but only to pre-light injury levels [ 139 ]. A different study, using a cone and rod degenerative model, showed that Müller glial cells exhibited reactive gliosis before eventually transitioning into a regenerative state a few weeks following photoreceptor cell death due to activation by TNFα signalling [ 140 ].…”