The Role of Pendrin in the Development of the Murine Inner Ear

Wangemann, Philine

doi:10.1159/000335113

Cited by 35 publications

(34 citation statements)

References 51 publications

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“…Together, these results indicate that Ci-Slc26aα is present at the apical/luminal domain of lumen-forming cells. The presence of Ci-Slc26aα in the sensory vesicle epithelium and otolith is similar to the expression of mammalian SLC26A4 (also known as pendrin, after Pendred syndrome), in the epithelia of the vestibular labyrinth and the endolymphatic sac (22), which are responsible for sensing spatial orientation.…”

Section: Ci-slc26aαmentioning

confidence: 68%

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Anion translocation through an Slc26 transporter mediates lumen expansion during tubulogenesis

Deng

Nies

Feuer

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Lumen formation is a critical event in biological tube formation, yet its molecular mechanisms remain poorly understood. Specifically, how lumen expansion is coordinated with other processes of tubulogenesis is not well known, and the role of membrane transporters in tubulogenesis during development has not been adequately addressed. Here we identify a solute carrier 26 (Slc26) family protein as an essential regulator of tubulogenesis using the notochord of the invertebrate chordate Ciona intestinalis as a model. Ci-Slc26aα is indispensable for lumen formation and expansion, but not for apical/luminal membrane formation and lumen connection. Ci-Slc26aα acts as an anion transporter, mediating the electrogenic exchange of sulfate or oxalate for chloride or bicarbonate and electroneutral chloride:bicarbonate exchange. Mutant rescue assays show that this transport activity is essential for Ci-Slc26aα's in vivo function. Our work reveals the consequences and relationships of several key processes in lumen formation, and establishes an in vivo assay for studying the molecular basis of the transport properties of SLC26 family transporters and their related diseases. Biological tubular systems serve essential functions in embryogenesis, organogenesis, and adult physiology. The development of biological tubes is an interesting paradigm not only for biologists, but also for physicians, given that many devastating diseases are caused by failure of proper tubulogenesis or malfunction of tubular structures (1). A biological tube, in its simplest configuration, is composed of an epithelium enclosing a lumen. The tubular epithelium can either arise from a preexisting epithelium by wrapping or budding, or develop de novo from nonepithelial cells. In the latter case, nonepithelial cells undergo a mesenchymal-to-epithelial transition and become polarized, with a portion of the cell membrane, the apical domain, coming into direct contact with the future lumen (2). Exocytosis at the apical/luminal domain contributes to both apical membrane biogenesis and initial lumen formation.Recently, several transmembrane proteins, including transporters, pumps, and channels localized in the developing tubular epithelia, have been implicated in lumen expansion and tube size control (3). Among these, claudin and Na + K + -ATPase regulate lumen size in the development of the zebrafish gut (4) and the Drosophila trachea (5, 6) through their junctional activity. Interestingly, at least for Na + K + -ATPase, its pumping activity is dispensable (5). A bona fide apical transporter has not yet been identified and implicated in lumen expansion.Transepithelial ion transport is critically important for luminal fluid secretion and absorption in many tubular structures. The solute carrier 26 (SLC26) sulfate transporters, so-called because the first member, SLC26A1, was identified as a liver SO 4 2− transporter (7), compose a family of multidomain transmembrane anion exchangers capable of transporting a wide range of monovalent and divalent anions (8). Most ...

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Section: Ci-slc26aαmentioning

confidence: 68%

“…Mammalian SLC26A4 is also involved in ion homeostasis of the inner ear fluids. Patients with Pendred syndrome, caused by mutations in SLC26A4, have an enlarged vestibular aqueduct resulting from disruption of the balance between fluid secretion in the vestibular labyrinth and fluid absorption in the endolymphatic sac (22).…”

Section: Ci-slc26aαmentioning

confidence: 99%

Anion translocation through an Slc26 transporter mediates lumen expansion during tubulogenesis

Deng

Nies

Feuer

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…Whether specific inhibitors of pendrin can adversely affect the function of inner ear and thyroid, two organs with abundant expression of pendrin (22,30), remains speculative. Pendrin is essential for the embryonic development of structures involved in normal hearing (cochlea, the vestibular labyrinth, and the endolymphatic sac of the inner ear) (22,30), and its mutation in humans or in its deletion in mice causes structural abnormalities in the above organs during their embryonic stage, which results in deafness (30).…”

Section: Discussionmentioning

confidence: 99%

“…Pendrin is essential for the embryonic development of structures involved in normal hearing (cochlea, the vestibular labyrinth, and the endolymphatic sac of the inner ear) (22,30), and its mutation in humans or in its deletion in mice causes structural abnormalities in the above organs during their embryonic stage, which results in deafness (30). It is, therefore, highly plausible that the inhibition of pendrin after the normal development of inner-ear structures is completed will not interfere with normal hearing.…”

Section: Discussionmentioning

confidence: 99%

Double knockout of pendrin and Na-Cl cotransporter (NCC) causes severe salt wasting, volume depletion, and renal failure

Soleimani

Barone

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

110

140

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The Na-Cl cotransporter (NCC), which is the target of inhibition by thiazides, is located in close proximity to the chloride-absorbing transporter pendrin in the kidney distal nephron. Single deletion of pendrin or NCC does not cause salt wasting or excessive diuresis under basal conditions, raising the possibility that these transporters are predominantly active during salt depletion or in response to excess aldosterone. We hypothesized that pendrin and NCC compensate for loss of function of the other under basal conditions, thereby masking the role that each plays in salt absorption. To test our hypothesis, we generated pendrin/NCC double knockout (KO) mice by crossing pendrin KO mice with NCC KO mice. Pendrin/NCC double KO mice displayed severe salt wasting and sharp increase in urine output under basal conditions. As a result, animals developed profound volume depletion, renal failure, and metabolic alkalosis without hypokalemia, which were all corrected with salt replacement. We propose that the combined inhibition of pendrin and NCC can provide a strong diuretic regimen without causing hypokalemia for patients with fluid overload, including patients with congestive heart failure, nephrotic syndrome, diuretic resistance, or generalized edema.diuretics | kidney tubules | nephrogenic diabetes insipidus T he thiazide-sensitive Na-Cl cotransporter (NCC) (SLC12A3) and the Cl − /HCO 3 − exchanger pendrin (SLC26A4) are expressed on apical membranes of distal cortical nephron segments and mediate salt absorption, with pendrin working in tandem with the epithelial Na channel and NCC working by itself (1-6). Pendrin is expressed on the apical membrane of intercalated cells in late distal convoluted tubule (DCT), connecting tubule (CNT), and the cortical collecting duct (CCD) (7-9). The thiazide-sensitive NCC is primarily expressed on the apical membrane of DCT cells (10,11).Single deletion of pendrin or NCC does not cause salt wasting or excessive diuresis under basal conditions (5,(12)(13)(14)(15). Indeed, even a mild degree of salt wasting has not been demonstrated in these two genetically engineered mouse models at steady state. Kidney functions, including sodium and chloride excretion, urine output, and blood urea nitrogen (BUN) levels in mutant mice are comparable to wild-type (WT) animals (12-15). Both pendrin KO and NCC KO mice, however, show signs of volume depletion or develop hypotension during salt restriction (12,14). These findings have led investigators to conclude that pendrin and NCC are predominantly active during salt depletion (and or in response to increased aldosterone levels), and their contribution to salt reabsorption at baseline conditions is small.We hypothesized that NCC and pendrin may compensate for loss of the other under basal conditions, thereby masking the role that each plays in salt reabsorption. To test this hypothesis, we generated double knockout of pendrin and NCC mice by crossing animals with single deletion for NCC and pendrin. The double KO mice show significant salt and flui...

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“…In the inner ear, pendrin was found in specific subsets of non-sensory cells within the cochlea, endolymphatic duct and sac and vestibular labyrinth, where it functions as a Cl - /HCO 3 - exchanger and controls the pH and volume of the endolymph [24]. In the last ten years, the work of Wangemann and colleagues illuminated the role of pendrin in the physiology of development of the inner ear [24,25,26,27,28,29,30,31,32,33,34].…”

Section: B) the Second Biannual Meeting Of The Pendrin Consortiummentioning

confidence: 99%

Synopsis of the 48^thAnnual Meeting of the Lake Cumberland Biological Transport Group and the Second Biannual Meeting of the Pendrin Consortium

Dossena

Nofziger

Morabito

et al. 2013

Cell Physiol Biochem

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Ion transporters are the molecular basis for ion homeostasis of the cell and the whole organism. The anion exchanger pendrin is only one of a number of examples where a complete or partial loss of function and/or deregulation of expression of ion transporters may lead or contribute to pathological conditions in humans. A complete understanding of the function of ion transporters in health and disease may pave the way for the identification of new and focused therapeutic approaches. Exchange of knowledge and connectivity between the experts in the feld of transport physiology is essential in facing these challenging tasks. The Lake Cumberland Biological Transport Group and the Pendrin Consortium are examples of scientific forums where investigators combine their efforts towards a better understanding of molecular pathophysiology of ion transport. This issue discusses the versatility of ion transporters involved in the regulation of cellular volume and other functions, such as the solute carrier (SLC) 12A gene family members SLC12A4-7, encoding the Na⁺-independent cation-chloride cotransporters commonly known as the K⁺-Cl^- cotransporters KCC1-4, and the betaine/γ-aminobutyric acid transport system (BGT1, SLC6A12), just to name a few. The issue further addresses the pathophysiology of intestinal and respiratory epithelia and related therapeutic tools and techniques to investigate interactions between proteins and proteins and small compounds. Finally, the current knowledge and new findings on the expression, regulation and function of pendrin (SLC26A4) in the inner ear, kidney, airways and blood platelets are presented.

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The Role of Pendrin in the Development of the Murine Inner Ear

Cited by 35 publications

References 51 publications

Anion translocation through an Slc26 transporter mediates lumen expansion during tubulogenesis

Anion translocation through an Slc26 transporter mediates lumen expansion during tubulogenesis

Double knockout of pendrin and Na-Cl cotransporter (NCC) causes severe salt wasting, volume depletion, and renal failure

Synopsis of the 48^thAnnual Meeting of the Lake Cumberland Biological Transport Group and the Second Biannual Meeting of the Pendrin Consortium

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The Role of Pendrin in the Development of the Murine Inner Ear

Cited by 35 publications

References 51 publications

Anion translocation through an Slc26 transporter mediates lumen expansion during tubulogenesis

Anion translocation through an Slc26 transporter mediates lumen expansion during tubulogenesis

Double knockout of pendrin and Na-Cl cotransporter (NCC) causes severe salt wasting, volume depletion, and renal failure

Synopsis of the 48thAnnual Meeting of the Lake Cumberland Biological Transport Group and the Second Biannual Meeting of the Pendrin Consortium

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Synopsis of the 48^thAnnual Meeting of the Lake Cumberland Biological Transport Group and the Second Biannual Meeting of the Pendrin Consortium