Abstract
Mutations in tubby like protein 1 gene (TULP1) are causative of early-onset recessive inherited retinal degenerations (IRDs); similarly, the Tulp1-/- mouse is also characterized by a rapid IRD. Tulp1 mRNA and protein expression was analyzed in wild type mouse retinas and expression data sets (NCBI) during early postnatal development. Comparative histology was undertaken in Tulp1-/-, rhodopsin-/- (Rho-/-) and retinal degeneration slow-/- (Rds-/-) mouse retinas. Bioinformatic analysis of predicted TULP1 interactors and IRD genes was performed. Peak expression of Tulp1 in healthy mouse retinas was detected at p8; of note, TULP1 was detected in both the outer and inner retina. Bioinformatic analysis indicated Tulp1 expression in retinal progenitor, photoreceptor and non-photoreceptor cells. While common features of photoreceptor degeneration were detected in Tulp1-/-, Rho-/-, and Rds-/- retinas, other alterations in bipolar, amacrine and ganglion cells were specific to Tulp1-/- mice. Additionally, predicted TULP1 interactors differed in various retinal cell types and new functions for TULP1 were suggested. A pilot bioinformatic analysis indicated that in a similar fashion to Tulp1, many other IRD genes were expressed in both inner and outer retinal cells at p4–p7. Our data indicate that expression of Tulp1 extends to multiple retinal cell types; lack of TULP1 may lead to primary degeneration not only of photoreceptor but also non-photoreceptor cells. Predicted interactors suggest widespread retinal functions for TULP1. Early and widespread expression of TULP1 and some other IRD genes in both the inner and outer retina highlights potential hurdles in the development of treatments for these IRDs.
Highlights
Mutation in over 300 genes have been identified as causative of inherited retinal degenerations (IRDs) (Duncan et al, 2018; RetNet - Retinal Information Network, 2019) affecting 1 in 3000, or more than 2 million people worldwide (Sahel et al, 2015; Farrar et al, 2017)
We evaluated the architecture of Tulp1-/- retinas compared to retinas from Rho-/- (Humphries et al, 1997) and retinal degeneration slow (Rds-/-) (Sanyal et al, 1980) mice, where retinal degeneration is believed to originate from photoreceptors
tubby like protein 1 gene (TULP1) was distributed in the perikaryon, inner segment and synapse of developing photoreceptors by p8 (Figures 1e,f), which became largely confined to the inner segments and the synaptic ribbons in wt retinas by p14–p30 (Figures 1i,j,m,n); reflecting previous studies (Hagstrom et al, 1999; Xi et al, 2005)
Summary
Mutation in over 300 genes have been identified as causative of inherited retinal degenerations (IRDs) (Duncan et al, 2018; RetNet - Retinal Information Network, 2019) affecting 1 in 3000, or more than 2 million people worldwide (Sahel et al, 2015; Farrar et al, 2017). Mutations in tubby like protein 1 gene (TULP1) are causative of rare, early onset, severe forms of autosomal recessive retinal degeneration, usually diagnosed as Leber congenital amaurosis 15 (LCA15) or retinitis pigmentosa 14 (RP14) (RetNet Retinal Information Network, 2019). Tulp1-/- mice exhibit an early and severe retinal degeneration akin to the human condition; shortening of photoreceptor segments and swollen extruded mitochondria by postnatal day (p) (Ikeda et al, 2000); abnormal ribbon synaptic architecture by p13–p16 (Grossman et al, 2009); shortening of bipolar cell dendrites with less branching and compromised b-wave electroretinogram (ERG) by p16 (Grossman et al, 2009); reduced rod and cone ERGs by week 4 (Hagstrom et al, 1999; Ikeda et al, 2000); photoreceptor apoptosis from p18 (Ikeda et al, 2000) resulting in complete loss of the outer nuclear layer (ONL) by week 20 (Hagstrom et al, 1999; Ikeda et al, 2000)
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