Stem-loop binding protein is required for retinal cell proliferation, neurogenesis, and intraretinal axon pathfinding in zebrafish

Abstract

In the developing retina, neurogenesis and cell differentiation are coupled with cell proliferation. However, molecular mechanisms that coordinate cell proliferation and differentiation are not fully understood. In this study, we found that retinal neurogenesis is severely delayed in the zebrafish stem-loop binding protein (slbp) mutant. SLBP binds to a stem-loop structure at the 3'-end of histone mRNAs, and regulates a replication-dependent synthesis and degradation of histone proteins. Retinal cell proliferation becomes slower in the slbp1 mutant, resulting in cessation of retinal stem cell proliferation. Although retinal stem cells cease proliferation by 2 days postfertilization (dpf) in the slbp mutant, retinal progenitor cells in the central retina continue to proliferate and generate neurons until at least 5dpf. We found that this progenitor proliferation depends on Notch signaling, suggesting that Notch signaling maintains retinal progenitor proliferation when faced with reduced SLBP activity. Thus, SLBP is required for retinal stem cell maintenance. SLBP and Notch signaling are required for retinal progenitor cell proliferation and subsequent neurogenesis. We also show that SLBP1 is required for intraretinal axon pathfinding, probably through morphogenesis of the optic stalk, which expresses attractant cues. Taken together, these data indicate important roles of SLBP in retinal development.

Molecular characterization and expression of an oocyte-specific histone stem-loop binding protein in Carassius gibelio

“…In early embryos of D. rerio, Imai et al (2014) observed slbp2 expression in the 8-cell stage embryos, but did not examine its transcript after 31 h. Thereby, Imai and colleagues suggested that D. rerio slbp2 might be mainly expressed maternally. In this study, we have characterized an oocyte-specific slbp2 in C. gibelio, and revealed its dynamic expression pattern during oogenesis and embryogenesis.…”

“…c o m / l o c a t e / c b p b bovine SLBP2 was also found to express abundantly in oocytes and to accumulate preferentially in germinal vesicle (GV) of mature eggs and the nucleus of blastomeres (Thelie et al, 2012). Recently, Imai et al (2014) investigated the functional role of SLBP1 for retinal cell proliferation, neurogenesis, and intraretinal axon pathfinding in D. rerio embryos, and also checked a possible existence of maternal SLBP2 in the early embryos. Up to now, however, no oocyte-specific SLBP have been characterized in fish.…”

Abrogation of Stem Loop Binding Protein (Slbp) function leads to a failure of cells to transition from proliferation to differentiation, retinal coloboma and midline axon guidance deficits

“…Supporting the possibility that the causative mutation is in slbp, embryos injected with a splice-site morpholino, targeting the exon3-to-intron3 donor site in slbp, phenocopied various aspects of the ele phenotype including the morphological dent caudal to the MHB and coloboma (data not shown). Furthermore, another published mutation (slbp rw440 ) in slbp has been shown to cause retinal defects [10].…”

“…To better understand how compromised Slbp function may lead to slbp ty77e phenotypes, we analysed the spatial and temporal expression of slbp and the paralogous slbp2 gene. slbp and slbp2 transcripts are maternally expressed and ubiquitously distributed in early cleavage stage embryos ( Fig 1F-H and [10]). slbp2 transcripts are undetectable by in situ hybridization from 50% epiboly stage but continue to be detected by RT-PCR until 4-8 somite stage suggesting gradual depletion of a maternal transcript pool (Fig 1F,G).…”

“…Transcriptomic analysis at MBT in Drosophila showed zygotic gene activation to be severely compromised [29]. Disruption of Slbp function at later stages has revealed some surprising phenotypes that suggest unexpectedly cell-type-specific roles: in Drosophila, most slbp homozygous null mutants perish at late pupal stage but some survive to adulthood and show female sterility [24]; loss of Cdl-1 (Slbp) in C. elegans results in defects in pharynx morphogenesis and body elongation [23]; and, in zebrafish slpb mutants survive until 5dpf and present defects in retinal development [10].…”