Cellular Signaling by Fibroblast Growth Factors (FGFs) and Their Receptors (FGFRs) in Male Reproduction

Cotton, Leanne M.; O'Bryan, Moira K; Hinton, Barry T.

doi:10.1210/er.2007-0028

Cited by 101 publications

(101 citation statements)

References 286 publications

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“…13 However, accumulating evidence indicates that FGFs may also play an important role in cardiovascular regulation. Indeed, data from genetic and molecular studies implicated FGF1 and two other FGFs (FGF2 and FGF5) as potential players in human essential and pulmonary hypertension.…”

Section: Discussionmentioning

confidence: 99%

Pathway Analysis Shows Association between FGFBP1 and Hypertension

Tomaszewski¹,

Charchar²,

Nelson³

et al. 2011

Journal of the American Society of Nephrology

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Variants in the gene encoding fibroblast growth factor 1 (FGF1) co-segregate with familial susceptibility to hypertension, and glomerular upregulation of FGF1 associates with hypertension. To investigate whether variants in other members of the FGF signaling pathway may also associate with hypertension, we genotyped 629 subjects from 207 Polish families with hypertension for 79 single nucleotide polymorphisms in eight genes of this network. Family-based analysis showed that parents transmitted the major allele of the rs16892645 polymorphism in the gene encoding FGF binding protein 1 (FGFBP1) to hypertensive offspring more frequently than expected by chance (P ϭ 0.005). An independent cohort of 807 unrelated Polish subjects validated this association. Furthermore, compared with normotensive subjects, hypertensive subjects had approximately 1.5-and 1.4-fold higher expression of renal FGFBP1 mRNA and protein (P ϭ 0.04 and P ϭ 0.001), respectively. By immunohistochemistry, hypertensionrelated upregulation of FGFBP1 was most apparent in the glomerulus and juxtaglomerular space. Taken together, these data suggest that FGFBP1 associates with hypertension and that systematic analysis of signaling pathways can identify previously undescribed genetic associations. 22: 947-955, 201122: 947-955, . doi: 10.1681 Essential hypertension is a complex, multifactorial, heritable disease. The contribution of genetic factors to the development of hypertension is estimated at 30 to 50%, but the causative alleles and related molecular mechanisms remain largely elusive. However, it is becoming increasingly clear that genes underlying familial susceptibility to essential hypertension may not necessarily reside within the most obvious pathways involved in BP regulation. 1 Indeed, a substantial proportion of novel alleles associated with hypertension and BP in the recent genome-wide association scans map to genes that do not belong to classical systems of BP regulation (such as the sympathetic nervous system or renal sodium handling). 2,3 Fibroblast growth factor (FGF) family is an example of a novel group of mole- J Am Soc Nephrol

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Section: Discussionmentioning

confidence: 99%

Pathway Analysis Shows Association between FGFBP1 and Hypertension

Tomaszewski¹,

Charchar²,

Nelson³

et al. 2011

Journal of the American Society of Nephrology

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“…This may be due to decrease in the number of sperm or sperm not working properly, such as abnormal sperm motility and capacitation ability and other environmental or genetic problems [17]. It has been shown previously that sperm cell function and motility are regulated by a host of hormones and growth factors such as testosterone [18], epidermal growth factor (EGF) [19] and fibroblast growth factor (FGF) [20]. Indeed, through our sperm motility and function assays in this paper, we add NGF as another important molecule in sperm function and motility.…”

Section: Jin Et Al 442mentioning

confidence: 99%

Effect of NGF on the Motility and Acrosome Reaction of Golden Hamster Spermatozoa In Vitro

Wei

Tanaka

Watanabe

et al. 2010

Journal of Reproduction and Development

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Abstract. Motility and fertilizing ability are known to be two important physiological attributes of a mature sperm, yet the mechanism by which spermatozoa mature and become motile remains largely unknown. It has been shown that nerve growth factor (NGF) is a protein essential for the development, maintenance and survival of the peripheral and central nervous systems. However, the presence of high levels of NGF protein and mRNA do not correlate with the innervations by NGF sensitive fibers in tissues such as the testis, prostate and seminal vesicles. These observations have shifted the attention of research to the role of NGF outside of the nervous system. Here, we demonstrate that NGF and its receptors TrkA and p75 are widely expressed in the testis, accessory reproductive organ, and the epididymal sperms. We also show that NGF stimulates two important aspects of sperm functions, motility and the acrosome reaction, in a time-and dose-dependent manner. NGF activated the sperm cell acrosome reaction, while addition of inhibitors specific for MAPK kinase significantly blocked the sperm acrosome reaction. Taken together, our findings suggest that NGF plays an integral role in sperm motility and the acrosome reaction through, at least in part, the MAPK signalling pathway. Key words: Acrosome reaction, Golden hamster, Motility, Nerve growth factor (NGF), Sperm (J. Reprod. Dev. 56: [437][438][439][440][441][442][443] 2010) everal reports have established that the neurotropins, which include NGF, brain-derived neurotropic factor (BDNF), NT-3, NT-4 and NT-5, are essential factors concerning the development and maintenance of sympathetic and sensory peripheral neurons as well as central cholinergic neurons [1]. Effects of NGF have been shown to be mediated through specific membrane receptors of low-(p75) and high-(TrkA) affinity, the latter being responsible for most of its biological activities on neuronal tissues [1] and others [2][3][4].Each neurotrophin binds a specific Trk receptor tyrosine kinase [5], and its binding to Trk receptors results in receptor dimerization and kinase activation. Trk receptor phosphorylation promotes signaling cascades by creating docking sites for adaptor proteins that couple these receptors to pathways such as the Ras/extracellularsignal-regulated protein kinase (ERK) and mitogen-activated protein kinase (MAPK) pathways [6].Despite the central tropic effect of neurotrophins in the nervous system, high levels of NGF have been reported to exist outside the nervous system, particularly in the testis [7,8]. In addition, a substantial number of observations linking NGF to sperm development have been reported: high levels of NGF mRNA have been discovered in the lower mouse caput epididymis and corpus epididymis, suggesting a role for NGF in sperm maturation [7], testicular and germ cell atrophy following exposure to n-hexane leads to loss of NGF [9] and NGF has been found to be synthesized by spermatocytes and early spermatids [7]. NGF has already been implicated in sperm cell survival eith...

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“…Overlapping and interconnected actions of E 2 (in the present study), androgens (Hamzeh & Robaire 2011), and growth factors (reviewed by Cotton et al 2008) on ERK1/2 activation may occur in the epididymis. An imbalance of these actions may result in infertility, and much remains to be learned about the complex interplay of hormonal actions in the epididymis.…”

Section: Discussionmentioning

confidence: 60%

Estrogen receptor ESR1 mediates activation of ERK1/2, CREB, and ELK1 in the corpus of the epididymis

Cavalcanti

Lucas

Lazari

et al. 2015

Journal of Molecular Endocrinology

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Expression of the estrogen receptor ESR1 is higher in the corpus than it is in the initial segment/caput and cauda of the epididymis. ESR1 immunostaining in the corpus has been localized not only in the nuclei but also in the cytoplasm and apical membrane, which indicates that ESR1 plays a role in membrane-initiated signaling. The present study investigated whether ESR1 mediates the activation of rapid signaling pathways by estradiol (E 2 ) in the epididymis. We investigated the effect of E 2 and the ESR1-selective agonist (4,4 0 ,4 0 0 -(4-propyl-(1H)-pyrazole-1,3,5-triyl)trisphenol (PPT) on the activation of extracellular signal-regulated protein kinases (ERK1/2), CREB protein, and ETS oncogene-related protein (ELK1). Treatment with PPT did not affect ERK1/2 phosphorylation in the cauda, but it rapidly increased ERK1/2 phosphorylation in the initial segment/caput and corpus of the epididymis. PPT also activated CREB and ELK1 in the corpus of the epididymis. The PPT-induced phosphorylation of ERK1/2, CREB, and ELK1 was blocked by the ESR1-selective antagonist MPP and by pretreatment with a non-receptor tyrosine kinase SRC inhibitor, an EGFR kinase inhibitor, an MEK1/2 inhibitor, and a phosphatidylinositol-3-kinase inhibitor. In conclusion, these results indicate that the corpus, which is a region with high expression of the estrogen receptor ESR1, is a major target in the epididymis for the activation of rapid signaling by E 2 . The sequence of events that follow E 2 interaction with ESR1 includes the SRC-mediated transactivation of EGFR and the phosphorylation of ERK1/2, CREB, and ELK1. This rapid estrogen signaling may modulate gene expression in the corpus of the epididymis, and it may play a role in the dynamic microenvironment of the epididymal lumen.

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Cellular Signaling by Fibroblast Growth Factors (FGFs) and Their Receptors (FGFRs) in Male Reproduction

Cited by 101 publications

References 286 publications

Pathway Analysis Shows Association between FGFBP1 and Hypertension

Pathway Analysis Shows Association between FGFBP1 and Hypertension

Effect of NGF on the Motility and Acrosome Reaction of Golden Hamster Spermatozoa In Vitro

Estrogen receptor ESR1 mediates activation of ERK1/2, CREB, and ELK1 in the corpus of the epididymis

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