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

Neil Smyth,Bernhard L. Bader,Roswitha Nischt,Anton Page,Kerstin Böse,Mats Paulsson

doi:10.1074/jbc.m607886200

Abstract

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 gamma1 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.

Highlights

Members of the laminin, nidogen, proteoglycan, and collagen IV families, and basement membrane diversity is in part derived from the large numbers of differentially expressed isoforms of laminin and collagen IV [2]
Original theories suggested that the apical ectodermal ridge (AER),2 a thickening of the epithelium over the distal edge of the limb bud, is maintained by sonic hedgehog expressed by mesenchyme as part of a positive feedback loop
Are the growth factors retained in the extracellular matrix and so concentrated in specific regions, but they are protected from proteolytic degradation [17]

Summary

Introduction

Members of the laminin, nidogen, proteoglycan, and collagen IV families, and basement membrane diversity is in part derived from the large numbers of differentially expressed isoforms of laminin and collagen IV [2]. In agreement with the immunohistological findings, transmission electron microscopy of the developing limb bud at E10.5 showed that the basement membrane was present as a typical intact double layer under the epithelium of control animals (Fig. 6D).

Results

Conclusion