Neurologic Defects and Selective Disruption of Basement Membranes in Mice Lacking Entactin-1/Nidogen-1

Dong, Lijin; Chen, Yong; Lewis, Marcia; Hsieh, Jyh Cheng; Reing, Janet E.; Chaillet, J. Richard; Howell, Carina Y.; Melhem, Mona F.; Inoué, Sadayuki; Kuszak, Jerry R.; DeGeest, Koen; Chung, Albert E.

doi:10.1097/01.lab.0000042240.52093.0f

Cited by 115 publications

(111 citation statements)

References 49 publications

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“…However, results from mice where this binding domain was deleted by gene targeting showed that nidogen-laminin binding, although important for the formation of certain basement membranes, is not a general prerequisite for basement membrane assembly (11). Genetic deletion of either of the nidogen genes in the mouse results in only mild changes with no alteration in tissue or basement membrane architecture (12)(13)(14). Further, the finding of a redistribution and up-regulation of nidogen-2 in nidogen-1-deficient animals suggested a partial redundancy within the family (13).…”

mentioning

confidence: 79%

Loss of Nidogen-1 and -2 Results in Syndactyly and Changes in Limb Development

Böse

Nischt

Page

et al. 2006

Journal of Biological Chemistry

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Nidogens are two ubiquitous basement membrane proteins produced mainly by mesenchymal cells. Nidogen-mediated interactions, in particular with laminin, collagen IV, and perlecan have been considered important in the formation and maintenance of the basement membrane. However, whereas mice lacking both nidogen isoforms or carrying mutations in the high affinity nidogen-binding site upon the laminin ␥1 chain have specific basement membrane defects in certain organs, particularly in the lung, characterization of these mice has also shown that basement membrane formation per se does not need nidogens or the laminin-nidogen interaction. Limb development requires the complex interplay of numerous growth factors whose expression is dependent upon the apical ectodermal ridge. Here, we show that lack of nidogen-1 and -2 results in a specific and time-limited failure in the ectodermal basement membrane of the limb bud. The absence of this basement membrane leads to aberrant apical ectodermal ridge formation. It also causes altered distribution of growth factors, such as fibroblast growth factors and leads to a fully penetrant soft tissue syndactyly caused by the dysregulation of interdigital apoptosis. Further, in certain animals more severe changes in bone formation occur, providing evidence for the interplay between growth factors and the extracellular matrix.

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confidence: 79%

Loss of Nidogen-1 and -2 Results in Syndactyly and Changes in Limb Development

Böse

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Page

et al. 2006

Journal of Biological Chemistry

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“…Because of the unavailability of entactin/nidogen, we could not investigate its role in MDCK cystogenesis in methylcellulose gels. We predict that nidogen alone would not be sufficient for MDCK cystogenesis, because the ablation of the nidogen gene displays neurological abnormalities but does not result in aberrant epithelial morphogenesis (Dong et al, 2002). …”

Section: Search For the Critical Cell-ecm Adhesion Event(s) In Mdck Cmentioning

confidence: 99%

The microenvironmental determinants for kidney epithelial cyst morphogenesis

Guo

Xia

Moshiach

et al. 2008

European Journal of Cell Biology

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Although epithelial morphogenesis is tightly controlled by intrinsic genetic programs, the microenvironment in which epithelial cells proliferate and differentiate also contributes to the morphogenetic process. The roles of the physical microenvironment in epithelial morphogenesis, however, have not been well dissected. In this study, we assessed the impact of the microenvironment on epithelial cyst formation, which often marks the beginning or end step of morphogenesis of epithelial tissues and the pathological characteristic of some diseases. Previous studies have demonstrated that Madin-Darby canine kidney (MDCK) epithelial cells form cysts when grown in a three-dimensional (3D) extracellullar matrix (ECM) environment. We have now further demonstrated that the presence of ECM in the 3D scaffold is required for the formation of properly polarized cysts. Also, we have found that the full interface of epithelial cells with the ECM environment (in-3D) is not essential for cyst formation, since partial contact (on-3D) is sufficient to induce cystogenesis. In addition, we have defined the minimal ECM environment or the physical threshold for cystogenesis under the on-3D condition. Only above the threshold can the morphological cues from the ECM environment induce cyst formation. Moreover, cyst formation under the on-3D condition described in this study actually defines a novel and more feasible model to analyze in vitro morphogenesis. Finally, we have found that, during cystogenesis, MDCK cells generate basal microprotrusions and produce vesicle-like structures to the basal extracellular space, which are specific to and correlated with cyst formation. For the first

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“…Nidogen is constitutively located in areas of epithelial-mesenchymal interactions where it is secreted by the resident fibroblasts (Fox et al, 1991;Marinkovich et al, 1993;Ekblom et al, 1994), which has been confirmed in experimental systems in vitro (Fleischmajer et al, 1995;Smola et al, 1998). In mammals two isoforms have been discovered, nidogen-1 which is the major form, and nidogen-2 (Kohfeldt et al, 1998), and knockout mice have been generated (Murshed et al, 2000;Dong et al, 2002;Schymeinsky et al, 2002) providing a more specific functional proof. The complete lack of either nidogen-1 or -2 did not produce an obvious phenotype in basement membrane structures or related functions.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of basement membrane formation by a nidogen-binding laminin γ1-chain fragment in human skin-organotypic cocultures

Breitkreutz

Mirancea

Schmidt

et al. 2004

Journal of Cell Science

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Basement membranes generally determine different tissue compartments in complex organs, such as skin, playing not only an important structural but also a regulatory role. We have previously demonstrated the formation of a regular basement membrane in organotypic three-dimensional (3D)-cocultures of human skin keratinocytes and fibroblasts by indirect immunofluorescence and transmission electron microscopy. In this assembly process, cross-linking of type IV collagen and the laminin γ1 chain by nidogen is considered a crucial step. For a functional proof, we have now competitively inhibited nidogen binding to laminin in 3D-cocultures with a recombinant laminin γ1 fragment (γ1III3-5 module) spanning this binding site. Repeated treatment abolished the deposition of nidogen at the epithelial-matrix interface but also greatly perturbed the presence of other matrix constituents such as laminin and perlecan. This effect persisted over the entire observation period of 10 to 21 days. In contrast, some components of the basement membrane zone were only moderately affected, with the laminin-5 isoform (γ2 chain), type IV collagen and integrin α6ß4 still showing a distinct staining at their regular position, when seen by light microscopy. Furthermore, epidermal morphology and differentiation remained largely normal as indicated by the regular location of keratins K1/K10 and also of late differentiation markers. Ultrastructural examination demonstrated that the γ1 fragment completely suppressed any formation of basement membrane structures (lamina densa) and also of hemidesmosomal adhesion complexes. As a consequence of hemidesmosome deficiency, keratin filament bundles were not attached to the ventral basal cell aspect. These findings were further substantiated by immuno-electron microscopy, revealing either loss or drastic reduction and dislocation of basement membrane and hemidesmosomal components. Taken together, in this simplified human skin model (representing a `closed system') a functional link has been demonstrated between compound structures of the extra- and intracellular space at the junctional zone providing a basis to interfere at distinct points and in a controlled fashion.

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Neurologic Defects and Selective Disruption of Basement Membranes in Mice Lacking Entactin-1/Nidogen-1

Cited by 115 publications

References 49 publications

Loss of Nidogen-1 and -2 Results in Syndactyly and Changes in Limb Development

Loss of Nidogen-1 and -2 Results in Syndactyly and Changes in Limb Development

The microenvironmental determinants for kidney epithelial cyst morphogenesis

Inhibition of basement membrane formation by a nidogen-binding laminin γ1-chain fragment in human skin-organotypic cocultures

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