Igf Binding Proteins Protect Undifferentiated Spermatogonia in the Zebrafish Testis Against Excessive Differentiation

Safian, Diego; Morais, Roberto D.V.S.; Bogerd, Jan; Schulz, Rüdiger

doi:10.1210/en.2016-1315

Cited by 34 publications

(49 citation statements)

References 61 publications

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“…Fsh promotes spermatogenesis by modulating LC (fishspecific, in context with the presence of the Fshr on LCs) and SC (in all vertebrates, in context with the presence of the Fshr on SCs) functions. A previous study showed that zebrafish Fsh activated, in an androgen-independent manner, the differentiating proliferation of type A spermatogonia, but did not change the proportion of A und while increasing the one for A diff spermatogonia (Safian et al 2016). However, it was not known how Fsh acts to prevent depletion of type A und spermatogonia.…”

Section: Discussionmentioning

confidence: 97%

“…We have reported previously that 100 ng/mL Fshstimulated both self-renewal division of A und and differentiating proliferation toward A diff spermatogonia (Nóbrega et al 2015, Safian et al 2016, the latter by activating β-catenin signaling via Igf3 (Safian et al 2018). To study the potential involvement of Wnt signaling in A und proliferation and accumulation (i.e.…”

Section: Tissue Culturementioning

confidence: 99%

“…We reported that Fsh stimulated both self-renewal and differentiating proliferation of type A spermatogonia in zebrafish (Nóbrega et al 2015, Safian et al 2016 and that Fsh stimulated the release of Igf3 that in turn activated β-catenin signaling to promote the differentiation of type A spermatogonia (Safian et al 2018). To study if the Wnt signaling system is involved in Fsh-stimulated self-renewal of A und , zebrafish testes were exposed to Fsh with or without XAV939, an inhibitor of the β-catenindependent pathway.…”

Section: Fsh-stimulated Proliferation and Accumulation Of A Und Is Fumentioning

confidence: 99%

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Fsh stimulates Leydig cell Wnt5a production, enriching zebrafish type A spermatogonia

Safian

Ryane

Bogerd

et al. 2018

Journal of Endocrinology

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Follicle-stimulating hormone (Fsh) modulates vertebrate spermatogenesis by regulating somatic cell functions in the testis. We have found previously that zebrafish Fsh stimulated the differentiating proliferation of type A undifferentiated spermatogonia (Aund) in an androgen-independent manner by regulating the production of growth factors and other signaling molecules in both Sertoli (SCs) and Leydig cells (LCs). For example, Fsh triggered the release of Igf3 that subsequently activated β-catenin signaling to promote the differentiating proliferation of Aund. In the present study, we report that Fsh moreover uses the non-canonical Wnt pathway to promote the proliferation and accumulation of Aund. Initially, we found that the stimulatory effect of Fsh on the proliferation activity of Aund was further strengthened when β-catenin signaling was inhibited, resulting in an accumulation of Aund. We then showed that this Fsh-induced accumulation of Aund was associated with increased transcript levels of the non-canonical Wnt ligand, wnt5a. In situ hybridization of insl3 mRNA, a gene expressed in LCs, combined with Wnt5a immunocytochemistry identified LCs as the cellular source of Wnt5a in the adult zebrafish testis. Addition of an antagonist of Wnt5a to incubations with Fsh decreased both the proliferation activity and the relative section area occupied by Aund, while an agonist of Wnt5a increased these same parameters for Aund. Taken together, our data suggest that Fsh triggered LCs to release Wnt5a, which then promoted the proliferation and accumulation of Aund. Hence, Fsh uses non-canonical Wnt signaling to ensure the production of Aund, while also triggering β-catenin signaling via Igf3 to ensure spermatogonial differentiation.

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Section: Discussionmentioning

confidence: 97%

Section: Tissue Culturementioning

confidence: 99%

Section: Fsh-stimulated Proliferation and Accumulation Of A Und Is Fumentioning

confidence: 99%

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Fsh stimulates Leydig cell Wnt5a production, enriching zebrafish type A spermatogonia

Safian

Ryane

Bogerd

et al. 2018

Journal of Endocrinology

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“…Because Pappaa acts to increase IGF1 bioavailability by freeing IGF1 from IGFBPs (Boldt and Conover, 2007), we asked whether this role was important for hair cell survival following neomycin exposure. To test this, we bathed wild type and pappaa p170 larvae in NBI-31772, an IGFBP inhibitor that stimulates IGF1 availability (Safian et al, 2016). Treatment with NBI-31772 for 24 hours prior to and during neomycin exposure improved hair cell survival in wild type and pappaa p170 larvae (Figure 3C).…”

Section: Resultsmentioning

confidence: 99%

Pregnancy-associated plasma protein-aa supports hair cell survival by regulating mitochondrial function

Alassaf

Daykin

Mathiaparanam

et al. 2019

Preprint

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19To support cell survival, mitochondria must balance energy production with oxidative stress. Inner 20 ear hair cells are particularly vulnerable to oxidative stress; thus require tight mitochondrial regulation. 21 We identified a novel molecular regulator of the hair cells' mitochondria and survival: Pregnancy-22 associated plasma protein-aa (Pappaa). Hair cells in zebrafish pappaa mutants exhibit mitochondrial 23 defects, including elevated mitochondrial calcium, transmembrane potential, and reactive oxygen 24 species (ROS) production and reduced antioxidant expression. In pappaa mutants, hair cell death is 25 enhanced by stimulation of mitochondrial calcium or ROS production and suppressed by a 26 mitochondrial ROS scavenger. As a secreted metalloprotease, Pappaa stimulates extracellular insulin-27 like growth factor 1 (IGF1) bioavailability. We found that the pappaa mutants' enhanced hair cell loss 28 can be suppressed by stimulation of IGF1 availability and that Pappaa-IGF1 signaling acts post-29 developmentally to support hair cell survival. These results reveal Pappaa as an extracellular regulator 30 of hair cell survival and essential mitochondrial function. 31 32Without a sufficient regenerative capacity, a nervous system's form and function critically depends 33 on the molecular and cellular mechanisms that support its cells' longevity. Neural cell survival is 34 inherently challenged by the nervous system's high energy demand, which is required to support basic 35 functions, including maintaining membrane potential, propagating electrical signals, and coordinating 36 the release and uptake of neurotransmitters (Halliwell, 2006; Kann and Kovács, 2007; Howarth et al., 37 2012). Metabolic energy is primarily supplied by mitochondrial oxidative phosphorylation (Kann and 38 Kovács, 2007). Although this process is essential to cell survival, a cytotoxic consequence is the 39 generation of reactive oxygen species (ROS). Oxidative stress caused by ROS accumulation damages 40 vital cell components including DNA, proteins, and lipids (Schieber and Chandel, 2014). Neural cells 41 are particularly vulnerable to oxidative stress due not only to their energy demand and thereby ROS 42 production, but also to their relatively insufficient antioxidant capacity (Halliwell, 1992). This 43 heightened susceptibility to oxidative stress-mediated cell death is believed to underlie aging and 44 neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), and 45 Amyotrophic lateral sclerosis (ALS) (Perry et al., 2002; Barber et al., 2006; Mattson and Magnus, 46 2006; Blesa et al., 2015). 47 Hair cells of the inner ear are a population of neural cells that are particularly susceptible to 48 oxidative stress-induced death (Gonzalez-Gonzalez, 2017) These specialized sensory cells relay sound 49 and balance information to the central nervous system. Hair cell death or damage, which is irreversible 50 in mammals, is the primary cause of hearing loss, and is exacerbated by ag...

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“…In male zebrafish, igf-3 promotes the proliferation and differentiation of type A undifferentiated spermatogonia. In a study by Safian et al (2016), an increase in igfbp-3 lead to a decrease in type A undifferentiated spermatogonia, the primary cells involved in spermatogenesis (De Paiva Camargo et al 2017). Further research indicated that igfbp-3 and igfbp-5 have opposing effects on controlling igf-3 bioactivity in zebrafish (Safian et al 2016).…”

Section: Discussionmentioning

confidence: 95%

Application of Molecular Pathology Techniques to Understand Mechanisms of Disease in Smallmouth Bass

Walsh¹

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In the Chesapeake Bay drainage, smallmouth bass Micropterus dolomieu are used as an indicator species of estrogenic contaminant exposure and have been implicated in fish kills and disease since 2005. In the Potomac River drainage, adult smallmouth bass have experienced mortality and disease and males have a high prevalence of intersex (testicular oocytes). Conversely, in the Susquehanna River drainage mortalities and disease of young-of-the-year smallmouth bass (YOY SMB) have occurred and resulted in a population shift to older and larger fish. The exact cause of these events remains unknown; however, factors such as poor water quality, contaminants, pathogens and parasites, increased temperatures, and nutrification have been assessed. In order to address this issue, the USGS Fish Health Branch, Leetown Science Center, and West Virginia Cooperative Fish and Wildlife Research Unit have ongoing assessment and monitoring projects throughout the Chesapeake Bay watershed. The use of routine histopathology has provided guidance for further research with molecular endpoints that may help explain the mechanisms involved in disease in smallmouth bass. The purpose of this dissertation research was to: 1.) Identify the prevalence of coinfections and risk factors of disease in YOY SMB; 2.) Use in situ hybridization to identify coinfections of bacteria with the myxozoan parasite Myxobolus inornatus in YOY smallmouth bass; 3.) Model liver helminths and coinfections of YOY SMB with land use at two spatial scales; 4.) Develop laser capture microdissection methods for nucleic acid extractions which could be used with smallmouth bass tissues; and 5.) Utilize Next-Generation Sequencing to develop a partial testes transcriptome to identify molecular markers that may help explain intersex development in male smallmouth bass. would like to thank the many people who have helped in the laboratory and in the field including Kathy Spring,

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Igf Binding Proteins Protect Undifferentiated Spermatogonia in the Zebrafish Testis Against Excessive Differentiation

Cited by 34 publications

References 61 publications

Fsh stimulates Leydig cell Wnt5a production, enriching zebrafish type A spermatogonia

Fsh stimulates Leydig cell Wnt5a production, enriching zebrafish type A spermatogonia

Pregnancy-associated plasma protein-aa supports hair cell survival by regulating mitochondrial function

Application of Molecular Pathology Techniques to Understand Mechanisms of Disease in Smallmouth Bass

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