Loss of Vascular Endothelial Growth Factor A (VEGFA) Isoforms in the Testes of Male Mice Causes Subfertility, Reduces Sperm Numbers, and Alters Expression of Genes That Regulate Undifferentiated Spermatogonia

Lu, Ningxia; Sargent, Kevin M.; Clopton, Debra T.; Pohlmeier, William E.; Brauer, Vanessa M.; McFee, Renee M.; Weber, John; Ferrara, Napoleone; Silversides, David W.; Cupp, Andrea S.

doi:10.1210/en.2013-1363

Cited by 43 publications

(39 citation statements)

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“…The BTB, established at postnatal day 15 in mice, 16 separates the mitotic/spermatogonial and meiotic/ spermatocyte compartment and undergoes remodeling at stage VIII of the seminiferous epithelial cell cycle to facilitate the transport of preleptotene spermatocytes across the barrier so that meiosis I/II and subsequent postmeiotic spermatid development can take place in the adluminal compartment behind the BTB. 1 We exploited the VEcadherin promoter for a conditional Cre recombinase deletion of Akap9 in the testes because in addition to its well known expression in endothelial cells, 17 VE-cadherin exhibits epithelial cycle stageespecific expression in the Sertoli cells 18,19 and in differentiating spermatids at stage II and elongated spermatids of mouse testes. 19 Conditional or global Akap9 deletion led to male infertility that could not be ascribed to a primary defect in spermatogenic cells or Sertoli cell maturation.…”

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confidence: 99%

AKAP9, a Regulator of Microtubule Dynamics, Contributes to Blood-Testis Barrier Function

Venkatesh

Mruk

Herter

et al. 2016

The American Journal of Pathology

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The blood-testis barrier (BTB), formed between adjacent Sertoli cells, undergoes extensive remodeling to facilitate the transport of preleptotene spermatocytes across the barrier from the basal to apical compartments of the seminiferous tubules for further development and maturation into spermatozoa. The actin cytoskeleton serves unique structural and supporting roles in this process, but little is known about the role of microtubules and their regulators during BTB restructuring. The large isoform of the cAMP-responsive scaffold protein AKAP9 regulates microtubule dynamics and nucleation at the Golgi. We found that conditional deletion of Akap9 in mice after the initial formation of the BTB at puberty leads to infertility. Akap9 deletion results in marked alterations in the organization of microtubules in Sertoli cells and a loss of barrier integrity despite a relatively intact, albeit more apically localized F-actin and BTB tight junctional proteins. These changes are accompanied by a loss of haploid spermatids due to impeded meiosis. The barrier, however, progressively reseals in older Akap9 null mice, which correlates with a reduction in germ cell apoptosis and a greater incidence of meiosis. However, spermiogenesis remains defective, suggesting additional roles for AKAP9 in this process. Together, our data suggest that AKAP9 and, by inference, the regulation of the microtubule network are critical for BTB function and subsequent germ cell development during spermatogenesis. (Am J Pathol 2016, 186: 270e284; http://dx

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confidence: 99%

AKAP9, a Regulator of Microtubule Dynamics, Contributes to Blood-Testis Barrier Function

Venkatesh

Mruk

Herter

et al. 2016

The American Journal of Pathology

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“…Research [Tüttelmann et al 2011;Lu et al 2013] clinical data, disease comorbidity, and 5) the reference (in review papers). Twelve examples of candidate genetic loci associated with male fertility presented according to our proposed standardized format are in Tables 3 and 4 [ Aston and Carrell 2009;Mashayekhi and Hadiyan 2012;Lai et al 2009;Lian et al 2009;Tüttelmann et al 2011;Escoffier et al 2015;Shen et al 2013;Lu et al 2013;Ramasamy et al 2014;Yakut et al 2013;He et al 2014;Luo et al 2014;Krausz et al 2012].…”

Section: Initiative For Standardization Of Reporting Genetics Of Malementioning

confidence: 99%

Initiative for standardization of reporting genetics of male infertility

Traven

Ogrinc

Kunej

2016

Systems Biology in Reproductive Medicine

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The number of publications on research of male infertility is increasing. Technologies used in research of male infertility generate complex results and various types of data that need to be appropriately managed, arranged, and made available to other researchers for further use. In our previous study, we collected over 800 candidate loci for male fertility in seven mammalian species. However, the continuation of the work towards a comprehensive database of candidate genes associated with different types of idiopathic human male infertility is challenging due to fragmented information, obtained from a variety of technologies and various omics approaches. Results are published in different forms and usually need to be excavated from the text, which hinders the gathering of information. Standardized reporting of genetic anomalies as well as causative and risk factors of male infertility therefore presents an important issue. The aim of the study was to collect examples of diverse genomic loci published in association with human male infertility and to propose a standardized format for reporting genetic causes of male infertility. From the currently available data we have selected 75 studies reporting 186 representative genomic loci which have been proposed as genetic risk factors for male infertility. Based on collected and formatted data, we suggested a first step towards unification of reporting the genetics of male infertility in original and review studies. The proposed initiative consists of five relevant data types: 1) genetic locus, 2) race/ethnicity, number of participants (infertile/controls), 3) methodology, 4) phenotype (clinical data, disease ontology, and disease comorbidity), and 5) reference. The proposed form for standardized reporting presents a baseline for further optimization with additional genetic and clinical information. This data standardization initiative will enable faster multi-omics data integration, database development and sharing, establishing more targeted hypotheses, and facilitating biomarker discovery.

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“…NRP1 can regulate adhesion and motility of endothelial cells by interacting with integrins and the non-receptor tyrosine kinase ABL1 (Fukasawa et al 2007;Murga et al 2005;Raimondi et al 2014;Valdembri et al 2009). Thus, VEGFA signaling plays a major role in testis vascularization and testis cord morphogenesis, but it is supported by other signaling pathways and potentially made redundant based on the observation that a pDmrt1-Cre-driven Vegfa knockout (excision of exon 3 specifically in the Sertoli and germ cells) does not prevent vascularization or testis cord formation (Lu et al 2013). …”

Section: Vegfa In Mesonephric Chemotaxismentioning

confidence: 99%

Mesonephric Cell Migration into the Gonads and Vascularization Are Processes Crucial for Testis Development

Romereim

Cupp

2016

Results and Problems in Cell Differentiation

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Testis morphogenesis requires the integration and reorganization of multiple cell types from several sources, one of the more notable being the mesonephric-derived cell population. One of the earliest sex-specific morphogenetic events in the gonad is a wave of endothelial cell migration from the mesonephros that is crucial for (1) partitioning the gonad into domains for testis cords, (2) providing the vasculature of the testis, and (3) signaling to cells both within the gonad and beyond it to coordinately regulate testis development. In addition to endothelial cell migration, there is evidence that precursors of peritubular myoid cells migrate from the mesonephros, an event which is also important for testis cord architecture. Investigation of the mesonephric cell migration event has utilized histology, lineage tracing with mouse genetic markers, and many studies of the signaling molecules/pathways involved. Some of the more well-studied signaling molecules involved include vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and neurotrophins. In this chapter, the morphogenetic events, relevant signaling pathways, mechanisms underlying the migration, and the role of the migratory cells within the testis will be discussed. Overall, the migration of mesonephric cells into the early testis is indispensable for its development and future functionality.

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Loss of Vascular Endothelial Growth Factor A (VEGFA) Isoforms in the Testes of Male Mice Causes Subfertility, Reduces Sperm Numbers, and Alters Expression of Genes That Regulate Undifferentiated Spermatogonia

Cited by 43 publications

References 42 publications

AKAP9, a Regulator of Microtubule Dynamics, Contributes to Blood-Testis Barrier Function

AKAP9, a Regulator of Microtubule Dynamics, Contributes to Blood-Testis Barrier Function

Initiative for standardization of reporting genetics of male infertility

Mesonephric Cell Migration into the Gonads and Vascularization Are Processes Crucial for Testis Development

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