Transepithelial Projections from Basal Cells Are Luminal Sensors in Pseudostratified Epithelia

Shum, Winnie; Silva, Nicolas Da; McKee, Mary; Smith, Peter J. S.; Brown, Dennis; Breton, Sylvie

doi:10.1016/j.cell.2008.10.020

Cited by 152 publications

(231 citation statements)

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“…During prepubertal development, the first wave of testicular luminal fluid enters the epididymis and activates the ERK pathway components in the initial-segment epithelium. The activated ERK pathway then promotes initial-segment differentiation (5), which is demonstrated by tall, columnar principal cells and long projections of basal cells (6,7). Efferent duct ligation prevents luminal fluid from entering the epididymis and abolishes the high activity levels of the ERK pathway components in the initial segment (5,8).…”

mentioning

confidence: 99%

PTEN signaling through RAF1 proto-oncogene serine/threonine kinase (RAF1)/ERK in the epididymis is essential for male fertility

Washington

Hinton

2014

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

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Without a fully developed initial segment, the most proximal region of the epididymis, male infertility results. Therefore, it is important to understand the development and regulation of this crucial region. In addition to distinctively high activity levels of the components of the ERK pathway, which are essential for initialsegment differentiation, the initial segment exhibits high protein and activity levels of phosphatase and tensin homolog (PTEN). To understand the role of PTEN in the regulation of the initial segment, we generated a mouse model with a conditional deletion of Pten from the epithelial cells of the proximal epididymis from postnatal day 17 (P17) onward. Shortly after Pten deletion, hypertrophy of the proximal epididymis became evident. Loss of Pten resulted in activation of the AKT (protein kinase B) pathway components from P28 onward, which in turn gradually suppressed RAF1 proto-oncogene serine/threonine kinase (RAF1)/ERK signaling through the interaction between AKT and RAF1. Consistent with progressive changes in RAF1/ERK signaling, loss of Pten progressively altered cell shape, size, organization, proliferation, and survival in the initial-segment epithelium and resulted in dedifferentiation and extensive epithelial folding. Most importantly, knockout males progressively lost fertility and became infertile from 6 to 12 mo. Spermatozoa from older knockout mice showed a lower percentage of motility and a higher percentage of flagellar angulation compared with controls, suggesting compromised sperm maturation. Therefore, under normal physiological conditions, PTEN suppresses AKT activity to maintain activation of the RAF1/ERK signaling pathway, which in turn maintains normal function of the initial segment and therefore, normal sperm maturation.S permatozoa enter the epididymis from the testes as immotile cells that are incapable of fertilization. During epididymal transit, a complex process called sperm maturation allows for conversion of spermatozoa into motile and fertilization-competent cells. The long, convoluted epididymal duct-which is ∼6 m long in humans and 1 m in mice (1)-provides a luminal fluid microenvironment that is necessary for sperm maturation (2).It is apparent that the most proximal region of the epididymis, the initial segment, plays an important role in sperm maturation. C-ros oncogene 1 (Ros1) knockout male mice that lacked prepubertal differentiation of the epididymal initial segment were healthy but infertile (3). Spermatozoa from Ros1 knockouts showed flagellar angulation, a defect in sperm maturation (4). Therefore, it is important to examine the mechanisms by which the initial segment develops, functions normally, and contributes to normal sperm maturation.The initial segment exhibits high activity levels of the ERK pathway components. The ERK pathway [also known as the RAF (RAF proto-oncogene serine/threonine kinases)/MEK/ERK pathway] is an intracellular protein kinase cascade containing at least MAPK3 and/or MAPK1 (commonly known as ERK1 and ERK2), a MAPKK (com...

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mentioning

confidence: 99%

PTEN signaling through RAF1 proto-oncogene serine/threonine kinase (RAF1)/ERK in the epididymis is essential for male fertility

Washington

Hinton

2014

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

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“…Making measurements within these volumes is challenging. New methods using the expression of reporter proteins, such as pHluorin 40 and luciferase, as well as functionalized fine and nano particles, offer promising approaches to documenting the chemical changes taking place in the complex architecture of tissues. With the increasing documentation of ectoenzymic processes, coupled to dynamic chemical and structural changes occurring in the minute volumes of the EICS, this domain deserves an increased prominence in our consideration of cell function and disease.…”

Section: Resultsmentioning

confidence: 99%

“…As we get closer to the membrane the physical chemistry gets progressively more complicated. 40 Nanometers from the membrane, such as within the membrane glycocalyx, new physical properties impact the chemical activity. Stock and Schwab (14) refer to this as a "shielded space" where molecular interactions can be fine tuned.…”

Section: J= -D φmentioning

confidence: 99%

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Windows to cell function and dysfunction: Signatures written in the boundary layers

Smith¹,

Collis²,

Messerli³

2010

BioEssays

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The medium surrounding cells either in culture or in tissues contains a chemical mix varying with cell state. As solutes move in and out of the cytoplasmic compartment they set up characteristic signatures in the cellular boundary layers. These layers are complex physical and chemical environments whose profiles both reflect cell physiology and provide conduits for intercellular messaging. Here we review some of the most relevant characteristics of the extracellular/intercellular space. Our initial focus is primarily with cultured cells but we extend our consideration to the far more complex environment of tissues and discuss how chemical signatures in the boundary layer can or may affect cell function. Critical to the entire essay are the methods used, or being developed, to monitor chemical profiles in the boundary layers. We review recent developments in ultramicro electrochemical sensors and tailored optical reporters suitable for the task 20 in hand. IntroductionThe advent of electron tomography with 3 dimensional image reconstruction has revealed a fundamental beauty and complexity behind the structure of the living cell. Notable contributions have come from several imaging laboratories but one of the most compelling can be found in Marsh et al.(1) From such reconstructions the complexity within a cell is quite staggering and in the 4 th dimension of time this entire structure is in motion. The question that becomes extremely interesting is how molecular and ionic signals are regulated and move within these matrices, where chemical diffusion will be significantly altered. (2) However, complexity, both structural and functional, does not stop at the plasma membrane but extends outwards 30 into the extracellular/intercellular space (EICS: Fig.1). The chemical dynamics within this space are hypothesized to play key roles in cancer, spreading depression, epilepsy and sleep disorders. (3)(4)(5)(6) The purpose of this essay is to consider what we can learn from this space and the methods for following the dynamics of chemical movement within the diffusive boundary layers that comprise an integral part of a cell. We will start by noting the physical and chemical features involved.

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“…These cells adhere to the basement membrane and it was believed that they do not have a direct access to the lumen of the duct (Hermo et al, 1994;Hermo and Robaire, 2002;Hess, 2002;Robaire, 2005). However, a recent study using three dimensional confocal imaging has identified that the epididymal basal cells extend long cytoplasmic projections that reach toward the lumen and thus are postulated to scan and chemically sense the luminal environment (Shum et al, 2008). Various functions have been attributed to basal cells including active protein secretion, endocytosis, a role in cell-mediated immune recognition and regulation of electrolyte and water transport (Cyr et al, 2002;Hermo and Robaire, 2002;Hess, 2002;Robaire, 2005;Wong et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Segment- And Cell-Specific Expression of Dtype Cyclins in the Postnatal Mouse Epididymis

Wang

2007

Biology of Reproduction

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Sperm transport, maturation and storage are the essential functions of the epididymis. The epididymis in the mouse is structurally characterized by regional and segmental organization including caput, corpus and cauda epididymis that are comprised of ten segments. Although several growth factor signaling pathways have been discovered in the epididymis, how these converge onto the cell cycle components is unknown. To begin to elucidate the growth factor control of cell cycle events in the epididymis, we analyzed the expression of D-type cyclins at different postnatal ages. At 7d, cyclin D1 was mainly expressed in the cauda epithelium, by 14d its expression occurred in the epithelium of caput, corpus and cauda that persisted up to 21d. By 42d, cyclin D1 was mostly detectable in the principal cells of the caput and corpus (segments 1-7) but not in the cauda epididymis. Expression of cyclin D2, unlike that of cyclin D1, was evident only at 42d but not earlier, and was mostly confined to corpus and cauda epithelium. In contrast to both cyclin D1 and D2, cyclin D3 was expressed primarily in the interstitium at 7d and by 21d its expression was localized to the epithelium of the corpus and cauda epididymis. By 42d, expression of cyclin D3 peaked in segments 6-10 and confined to basal and principal cells of the corpus and apical cells of the cauda epithelium. Ki67 immunoreactivity confirmed absence of cell proliferation despite continued expression of D-type cyclins in the adult epididymis. Collectively, on the basis of our immunophenotyping and protein expression data, we conclude that the D-type cyclins are expressed in a development -, segment-, and cell-specific manner in the postnatal mouse epididymis.

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Transepithelial Projections from Basal Cells Are Luminal Sensors in Pseudostratified Epithelia

Cited by 152 publications

References 56 publications

PTEN signaling through RAF1 proto-oncogene serine/threonine kinase (RAF1)/ERK in the epididymis is essential for male fertility

PTEN signaling through RAF1 proto-oncogene serine/threonine kinase (RAF1)/ERK in the epididymis is essential for male fertility

Windows to cell function and dysfunction: Signatures written in the boundary layers

Segment- And Cell-Specific Expression of Dtype Cyclins in the Postnatal Mouse Epididymis

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