Cystic fibrosis transmembrane conductance regulator protein expression in the male excretory duct system during development

Marcorelles, Pascale; Gillet, Danièle; Friocourt, Gaëlle; Ledé, Françoise; Samaison, Laura; Huguen, Geneviève; Férec, Claude

doi:10.1016/j.humpath.2011.04.031

Cited by 23 publications

(20 citation statements)

References 26 publications

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“…In previous studies, no obstruction was detected in the epididymis and vas deferens of human CF fetuses (Gaillard et al, 1997;Marcorelles et al, 2012). In addition, the epididymal abnormalities observed in infants and pre-pubertal boys with CF were reported to be less common than in adult CF patients (Blau et al, 2002;Gaillard et al, 1997;Oppenheimer and Esterly, 1969).…”

Section: Discussionmentioning

confidence: 86%

“…Therefore, epididymal and vas deferens dysfunction in patients with CF might be the result of a progressive atrophy of these tissues that might occur relatively late during development and reach maximum intensity in adulthood. Interestingly, although the epididymides of human CF fetuses were reported to have a normal morphological appearance by microscopy during the first 22 weeks of gestation, a breakdown of the epithelial wall, accompanied by infiltration of inflammatory cells, was detected in a human CF fetus at 26 weeks of gestation (Marcorelles et al, 2012). These focal areas of destruction were detected at a time when epithelial differentiation and apical accumulation of CFTR occur.…”

Section: Discussionmentioning

confidence: 99%

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CFTR interacts with ZO-1 to regulate tight junction assembly and epithelial differentiation via the ZONAB pathway

Ruan

Wang

Silva

et al. 2014

Journal of Cell Science

102

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Mutations in CFTR lead to dysfunction of tubular organs, which is currently attributed to impairment of its conductive properties. We now show that CFTR regulates tight junction assembly and epithelial cell differentiation through modulation of the ZO-1-ZONAB pathway. CFTR colocalizes with ZO-1 at the tight junctions of trachea and epididymis, and is expressed before ZO-1 in Wolffian ducts. CFTR interacts with ZO-1 through the CTFR PDZ-binding domain. In a three-dimensional (3D) epithelial cell culture model, CFTR regulates tight junction assembly and is required for tubulogenesis. CFTR inhibition or knockdown reduces ZO-1 expression and induces the translocation of the transcription factor ZONAB (also known as YBX3) from tight junctions to the nucleus, followed by upregulation of the transcription of CCND1 and downregulation of ErbB2 transcription. The epididymal tubules of cftr 2/2 and cftr DF508 mice have reduced ZO-1 levels, increased ZONAB nuclear expression, and decreased epithelial cell differentiation, illustrated by the reduced expression of apical AQP9 and V-ATPase. This study provides a new paradigm for the etiology of diseases associated with CFTR mutations, including cystic fibrosis.

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Section: Discussionmentioning

confidence: 86%

Section: Discussionmentioning

confidence: 99%

CFTR interacts with ZO-1 to regulate tight junction assembly and epithelial differentiation via the ZONAB pathway

Ruan

Wang

Silva

et al. 2014

Journal of Cell Science

102

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“…or low expression of CFTR in some parts of the brain, such as the cortex, hippocampus or hypothalamus, may be due to a delay in the appearance of the protein, as previously observed in other tissues (Marcorelles et al 2007;2012). In all structures, CFTR labeling in the CF case was only diffuse and cytoplasmic.…”

Section: (E) (F)mentioning

confidence: 56%

“…Negative controls were obtained by omission of the primary antibody or the use of other antibodies of known reactivity such as VEGF (Sentilhes et al 2010) or ARX, a transcription factor widely expressed in the developing brain and giving only nuclear labeling. In addition, the specificity of our CFTR labeling was carefully checked using different anti-CFTR antibodies (MAB3480 from Chemicon, Temecula, CA; MAB25031 and MAB1660 from R&D Systems, Abington, UK) and by testing them in parallel on lung, kidney and vas deferens sections (positive controls) and on heart and thymus sections (negative controls) (Todd-Turla et al 1996;Devuyst et al 1996;Marcorelles et al 2007;2012).…”

Section: Methodsmentioning

confidence: 99%

“…However, in the absence of clear genotype-phenotype correlations in CF, the developmental pattern of expression of CFTR has not been documented in organs that are not the major targets of the disease. As both peripheral and central neurological symptoms have sometimes been reported in patients with CF (Cavalier and Gambetti 1981;Cochran et al 1991;El-Salem et al 2010), we decided to investigate the expression of CFTR in the developing human CNS using immunohistochemistry and searched for, as previously described in the lung and male reproductive system (Marcorelles et al 2007;2012), possible differences in the expression and/or localization of the protein in deceased fetal and neonatal subjects with CF at different gestational ages.…”

Section: Introductionmentioning

confidence: 99%

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Cystic Fibrosis Transmembrane Conductance Regulator Protein (CFTR) Expression in the Developing Human Brain

Marcorelles

Friocourt

Uguen

et al. 2014

J Histochem Cytochem.

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SummaryCystic Fibrosis Transmembrane conductance Regulator (CFTR) protein has recently been shown to be expressed in the human adult central nervous system (CNS). As CFTR expression has also been documented during embryonic development in several organs, such as the respiratory tract, the intestine and the male reproductive system, suggesting a possible role during development we decided to investigate the expression of CFTR in the human developing CNS. In addition, as some, although rare, neurological symptoms have been reported in patients with CF, we compared the expression of normal and mutated CFTR at several fetal stages. Immunohistochemistry was performed on brain and spinal cord samples of foetuses between 13 and 40 weeks of gestation and compared with five patients with cystic fibrosis (CF) of similar ages. We showed in this study that CFTR is only expressed in neurons and has an early and widespread distribution during development. Although we did not observe any cerebral abnormality in patients with CF, we observed a slight delay in the maturation of several brain structures. We also observed different expression and localization of CFTR depending on the brain structure or the cell maturation stage. Our findings, along with a literature review on the neurological phenotypes of patients with CF, suggest that this gene may play previously unsuspected roles in neuronal maturation or function. (J Histochem Cytochem 62:791-801, 2014)

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Slc26a3 deficiency is associated with epididymis dysplasia and impaired sperm fertilization potential in the mouse

Khouri

Whitfield

Stouvenel

et al. 2018

Molecular Reproduction Devel

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Members of the solute carrier 26 (SLC26) family have emerged as important players in mediating anions fluxes across the plasma membrane of epithelial cells, in cooperation with the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel. Among them, SLC26A3 acts as a chloride/bicarbonate exchanger, highly expressed in the gastrointestinal, pancreatic and renal tissues. In humans, mutations in the SLC26A3 gene were shown to induce congenital chloride-losing diarrhea (CLD), a rare autosomal recessive disorder characterized by life-long secretory diarrhea. In view of some reports indicating subfertility in some male CLD patients together with SLC26-A3 and -A6 expression in the male genital tract and sperm cells, we analyzed the male reproductive parameters and functions of SLC26A3 deficient mice, which were previously reported to display CLD gastro-intestinal features. We show that in contrast to Slc26a6, deletion of Slc26a3 is associated with severe lesions and abnormal cytoarchitecture of the epididymis, together with sperm quantitative, morphological and functional defects, which altogether compromised male fertility. Overall, our work provides new insight into the pathophysiological mechanisms that may alter the reproductive functions and lead to male subfertility in CLD patients, with a phenotype reminiscent of that induced by CFTR deficiency in the male genital tract.

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Cystic fibrosis transmembrane conductance regulator protein expression in the male excretory duct system during development

Cited by 23 publications

References 26 publications

CFTR interacts with ZO-1 to regulate tight junction assembly and epithelial differentiation via the ZONAB pathway

CFTR interacts with ZO-1 to regulate tight junction assembly and epithelial differentiation via the ZONAB pathway

Cystic Fibrosis Transmembrane Conductance Regulator Protein (CFTR) Expression in the Developing Human Brain

Slc26a3 deficiency is associated with epididymis dysplasia and impaired sperm fertilization potential in the mouse

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