Modification of Crocodile Spermatozoa Refutes the Tenet That Post-testicular Sperm Maturation Is Restricted To Mammals*

Nixon, Brett; Johnston, Stephen D.; Skerrett‐Byrne, David A.; Anderson, Andy; Stanger, Simone J.; Bromfield, Elizabeth G.; Martin, Jacinta H.; Hansbro, Philip M.; Dun, Matthew D.

doi:10.1074/mcp.ra118.000904

Cited by 38 publications

(49 citation statements)

References 48 publications

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“…In the context of spermatozoa, the compartmentalization of cAMP signaling machinery coordinated by AKAP4 serves to regulate the specificity of signal transduction pathways responsible for the development, activation and maintenance of motility (Luconi et al, 2011;Sergeant et al, 2019). In accordance with this fundamental role, AKAP4 expression displays high evolutionary conservation, with Akap4 transcripts and/or immunoreactive orthologs of AKAP4 having been characterized in the testes and spermatozoa of species as phylogenetically diverse as eutherian mammals (humans, rodents, bovine, equine, porcine) (Johnson et al, 1997;Turner et al, 1998;Moss et al, 1999;Teijeiro and Marini, 2012;Blommaert et al, 2019;Sergeant et al, 2019), marsupials (tammar wallaby, opossum) (Hu et al, 2009), monotremes (platypus) (Hu et al, 2009), and reptiles (crocodile) (Nixon et al, 2019).…”

Section: Discussionmentioning

confidence: 96%

A Kinase Anchor Protein 4 Is Vulnerable to Oxidative Adduction in Male Germ Cells

Nixon

Bernstein

Cafe

et al. 2019

Front. Cell Dev. Biol.

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Oxidative stress is a leading causative agent in the defective sperm function associated with male infertility. Such stress commonly manifests via the accumulation of pathological levels of the electrophilic aldehyde, 4-hydroxynonenal (4HNE), generated as a result of lipid peroxidation. This highly reactive lipid aldehyde elicits a spectrum of cytotoxic lesions owing to its propensity to form stable adducts with biomolecules. Notably however, not all elements of the sperm proteome appear to display an equivalent vulnerability to 4HNE modification, with only a small number of putative targets having been identified to date. Here, we validate one such target of 4HNE adduction, A-Kinase Anchor Protein 4 (AKAP4); a major component of the sperm fibrous sheath responsible for regulating the signal transduction and metabolic pathways that support sperm motility and capacitation. Our data confirm that both the precursor (proAKAP4), and mature form of AKAP4, are conserved targets of 4HNE adduction in primary cultures of post-meiotic male germ cells (round spermatids) and in mature mouse and human spermatozoa. We further demonstrate that 4HNE treatment of round spermatids and mature spermatozoa results in a substantial reduction in the levels of both proAKAP4 and AKAP4 proteins. This response proved refractory to pharmacological inhibition of proteolysis, but coincided with an apparent increase in the degree of protein aggregation. Further, we demonstrate that 4HNE-mediated protein degradation and/or aggregation culminates in reduced levels of capacitation-associated phosphorylation in mature human spermatozoa, possibly due to dysregulation of the signaling framework assembled around the AKAP4 scaffold. Together, these findings suggest that AKAP4 plays an important role in the pathophysiological responses to 4HNE, thus strengthening the importance of AKAP4 as a biomarker of sperm quality, and providing the impetus for the design of an efficacious antioxidant-based intervention strategy to alleviate sperm dysfunction.

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Section: Discussionmentioning

confidence: 96%

A Kinase Anchor Protein 4 Is Vulnerable to Oxidative Adduction in Male Germ Cells

Nixon

Bernstein

Cafe

et al. 2019

Front. Cell Dev. Biol.

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“…This suggestion is consistent with the term's application by many contemporary reproductive biologists, and underlies the commonly proferred opinion that capacitation is a phenomenon predominantly restricted to mammals (e.g. Nixon et al ., , ). This explicitly restrictive use of ‘capacitation’ will avoid confusion that has arisen by some studies applying the term more generally to PEMS.…”

Section: Defining Pems and Suggested Nomenclaturementioning

confidence: 99%

Post‐ejaculatory modifications to sperm (PEMS)

Pitnick¹,

Wolfner

Dorus³

2019

Biological Reviews

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Mammalian sperm must spend a minimum period of time within a female reproductive tract to achieve the capacity to fertilize oocytes. This phenomenon, termed sperm ‘capacitation’, was discovered nearly seven decades ago and opened a window into the complexities of sperm–female interaction. Capacitation is most commonly used to refer to a specific combination of processes that are believed to be widespread in mammals and includes modifications to the sperm plasma membrane, elevation of intracellular cyclic AMP levels, induction of protein tyrosine phosphorylation, increased intracellular Ca2+ levels, hyperactivation of motility, and, eventually, the acrosome reaction. Capacitation is only one example of post‐ejaculatory modifications to sperm (PEMS) that are widespread throughout the animal kingdom. Although PEMS are less well studied in non‐mammalian taxa, they likely represent the rule rather than the exception in species with internal fertilization. These PEMS are diverse in form and collectively represent the outcome of selection fashioning complex maturational trajectories of sperm that include multiple, sequential phenotypes that are specialized for stage‐specific functionality within the female. In many cases, PEMS are critical for sperm to migrate successfully through the female reproductive tract, survive a protracted period of storage, reach the site of fertilization and/or achieve the capacity to fertilize eggs. We predict that PEMS will exhibit widespread phenotypic plasticity mediated by sperm–female interactions. The successful execution of PEMS thus has important implications for variation in fitness and the operation of post‐copulatory sexual selection. Furthermore, it may provide a widespread mechanism of reproductive isolation and the maintenance of species boundaries. Despite their possible ubiquity and importance, the investigation of PEMS has been largely descriptive, lacking any phylogenetic consideration with regard to divergence, and there have been no theoretical or empirical investigations of their evolutionary significance. Here, we (i) clarify PEMS‐related nomenclature; (ii) address the evolutionary origin, maintenance and divergence in PEMS in the context of the protracted life history of sperm and the complex, selective environment of the female reproductive tract; (iii) describe taxonomically widespread types of PEMS: sperm activation, chemotaxis and the dissociation of sperm conjugates; (iv) review the occurence of PEMS throughout the animal kingdom; (v) consider alternative hypotheses for the adaptive value of PEMS; (vi) speculate on the evolutionary implications of PEMS for genomic architecture, sexual selection, and reproductive isolation; and (vii) suggest fruitful directions for future functional and evolutionary analyses of PEMS.

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“…Like AML blast cells, LSCs require mutations in genes encoding for signaling proteins and transcription factors to promote overt AML [105,106]. Furthermore, LSCs are more chemoresistant than AML blast cells [26] making their characterization an important research endeavor.…”

Section: Relapse and Resistance Is Common In Flt3-itd Amlmentioning

confidence: 99%

“…Indeed, in 2017 the FDA approved the FLT3 inhibitor, Midostaurin in combination with standard of care chemotherapy for treatment of newly diagnosed FLT3-mutant AML patients [21], superseding an era of very little advancement in AML therapy [22].Despite the recurrence of FLT3 activating mutations in AML, the differences in oncogenic pathways in patients harboring either ITD or TKD mutations still requires clarification. The significant advancements recently made in unbiased quantitative phosphoproteomic profiling [23][24][25][26] has the potential to provide us with a full annotation of the signal pathways regulated in response to individual mutations, or following acquired resistance induced by 'dual lesions' (e.g. FLT3-ITD-TKD) [27].…”

mentioning

confidence: 99%

Targeting Oncogenic Signaling in Mutant FLT3 Acute Myeloid Leukemia: the Path to Least Resistance

Staudt¹,

Murray²,

Alvaro³

et al. 2018

Preprint

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Identification of recurrent driver mutations in genes encoding tyrosine kinases has resulted in the development of molecularly targeted strategies designed to improve the outcomes for patients diagnosed with acute myeloid leukemia (AML). The receptor tyrosine kinase FLT3, is the most commonly mutated gene in AML, with internal tandem duplications within the juxtamembrane domain (FLT3-ITD) or missense mutations in the tyrosine kinase domain (FLT3-TKD), present in 30%-35% of AML patients at diagnosis. An established driver mutation and marker of poor prognosis, the FLT3 tyrosine kinase has emerged as an attractive therapeutic target, and thus has encouraged the development of FLT3 tyrosine kinase inhibitors (TKIs). However, the therapeutic benefit of FLT3 inhibition, particularly as monotherapy, frequently results in the development of treatment resistance and disease relapse. Commonly, FLT3 inhibitor resistance is induced by the emergence of secondary lesions in the FLT3 gene, particularly in the second tyrosine kinase domain at residue Asp835 (D835) to form a ‘dual mutation’ (ITD-D835). Individual FLT3-ITD and FLT3-TKD mutations influence independent signaling cascades however, currently little is known which divergent signaling pathways are controlled by each of these FLT3 specific mutations, particularly in the context of patients harboring dual ITD-D835 mutations. This review provides a comprehensive analysis of the known discrete and cooperative signaling pathways regulated by each of the FLT3 specific mutations, as well as the therapeutic approaches that hold the most promise for development of more durable and personalized therapeutic approaches targeting mutant FLT3, to improve the treatment of AML.

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Modification of Crocodile Spermatozoa Refutes the Tenet That Post-testicular Sperm Maturation Is Restricted To Mammals*

Cited by 38 publications

References 48 publications

A Kinase Anchor Protein 4 Is Vulnerable to Oxidative Adduction in Male Germ Cells

A Kinase Anchor Protein 4 Is Vulnerable to Oxidative Adduction in Male Germ Cells

Post‐ejaculatory modifications to sperm (PEMS)

Targeting Oncogenic Signaling in Mutant FLT3 Acute Myeloid Leukemia: the Path to Least Resistance

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