Knockdown of Bardet-Biedl Syndrome Gene BBS9/PTHB1 Leads to Cilia Defects

Veleri, Shobi; Bishop, Kevin; Nogare, Damian E. Dalle; English, Milton A.; Foskett, Trevor J.; Chitnis, Ajay B.; Sood, Raman; Liu, Paul; Swaroop, Anand

doi:10.1371/journal.pone.0034389

Cited by 49 publications

(39 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Cell death did not appear to affect other ocular structures, as cornea and RPE, which highlighted that cerkl knockdown effects were restricted to the retina. Similar defects have also been observed for genes encoding transcription factors (e.g., math5, NR2E3) [50], [51], cell cycle regulators (e.g., Cdkn1b/c, cdk5) [52], and photoreceptor ciliary proteins (e.g., RPGR, RP2, TOPORS, BBS9) [53], [54], [55], [56]. Whether the shared phenotype reveals functional overlaps or secondary effects of retinal neurodegeneration, remains to be elucidated.…”

Section: Discussionmentioning

confidence: 70%

CERKL Knockdown Causes Retinal Degeneration in Zebrafish

Riera¹,

Burguera²,

Garcia‐Fernàndez³

et al. 2013

PLoS ONE

View full text Add to dashboard Cite

The human CERKL gene is responsible for common and severe forms of retinal dystrophies. Despite intense in vitro studies at the molecular and cellular level and in vivo analyses of the retina of murine knockout models, CERKL function remains unknown. In this study, we aimed to approach the developmental and functional features of cerkl in Danio rerio within an Evo-Devo framework. We show that gene expression increases from early developmental stages until the formation of the retina in the optic cup. Unlike the high mRNA-CERKL isoform multiplicity shown in mammals, the moderate transcriptional complexity in fish facilitates phenotypic studies derived from gene silencing. Moreover, of relevance to pathogenicity, teleost CERKL shares the two main human protein isoforms. Morpholino injection has been used to generate a cerkl knockdown zebrafish model. The morphant phenotype results in abnormal eye development with lamination defects, failure to develop photoreceptor outer segments, increased apoptosis of retinal cells and small eyes. Our data support that zebrafish Cerkl does not interfere with proliferation and neural differentiation during early developmental stages but is relevant for survival and protection of the retinal tissue. Overall, we propose that this zebrafish model is a powerful tool to unveil CERKL contribution to human retinal degeneration.

show abstract

Section: Discussionmentioning

confidence: 70%

CERKL Knockdown Causes Retinal Degeneration in Zebrafish

Riera¹,

Burguera²,

Garcia‐Fernàndez³

et al. 2013

PLoS ONE

View full text Add to dashboard Cite

show abstract

“…However, in contrast, bbs9 morphant zebrafish have an even more severe phenotype and the retina does not develop OS or discrete layers. 165 …”

mentioning

confidence: 99%

The role of primary cilia in the development and disease of the retina

2013

View full text Add to dashboard Cite

“…One TFBS candidate binds RFX7 , which plays an important role in the molecular cascade that controls ciliogenesis in the neural tube (Manojlovic, Earwood, Kato, Stefanovic, & Kato, ). This is of interest because we identified a strong association in our sNCS GWAS to BBS9 (Justice et al, ), a gene involved in the ciliopathies (Veleri et al, ). Another TFBS candidate binds SMAD3 and the finding that BMP2 stimulates the SMAD2/3 pathway (Wang et al, ) is consistent with the idea that increased BMP2 production is due to SMAD‐signaling.…”

Section: Discussionmentioning

confidence: 88%

A variant associated with sagittal nonsyndromic craniosynostosis alters the regulatory function of a non‐coding element

Justice

Kim

et al. 2017

American J of Med Genetics Pt A

Self Cite

View full text Add to dashboard Cite

Craniosynostosis presents either as a nonsyndromic congenital anomaly or as a finding in nearly 200 genetic syndromes. Our previous genome-wide association study of sagittal nonsyndromic craniosynostosis identified associations with variants downstream from BMP2 and intronic in BBS9. Because no coding variants in BMP2 were identified, we hypothesized that conserved non-coding regulatory elements may alter BMP2 expression. In order to identify and characterize noncoding regulatory elements near BMP2, two conserved noncoding regions near the associated region on chromosome 20 were tested for regulatory activity with a Renilla luciferase assay. For a 711 base pair noncoding fragment encompassing the most strongly associated variant, rs1884302, the luciferase assay showed that the risk allele (C) of rs1884302 drives higher expression of the reporter than the common allele (T). When this same DNA fragment was tested in zebrafish transgenesis studies, a strikingly different expression pattern of the green fluorescent reporter was observed depending on whether the transgenic fish had the risk (C) or the common (T) allele at rs1884302. The in vitro results suggest that altered BMP2 regulatory function at rs1884302 may contribute to the etiology of sagittal nonsyndromic craniosynostosis. The in vivo results indicate that differences in regulatory activity depend on the presence of a C or T allele at rs1884302.

show abstract

Knockdown of Bardet-Biedl Syndrome Gene BBS9/PTHB1 Leads to Cilia Defects

Cited by 49 publications

References 41 publications

CERKL Knockdown Causes Retinal Degeneration in Zebrafish

CERKL Knockdown Causes Retinal Degeneration in Zebrafish

The role of primary cilia in the development and disease of the retina

A variant associated with sagittal nonsyndromic craniosynostosis alters the regulatory function of a non‐coding element

Contact Info

Product

Resources

About