Matrix metalloproteinases in neural development: a phylogenetically diverse perspective

Abstract

The matrix metalloproteinases (MMPs) are a family of zinc-dependent endopeptidases originally characterized as secreted proteases responsible for degrading extracellular matrix proteins. Their canonical role in matrix remodelling is of significant importance in neural development and regeneration, but emerging roles for MMPs, especially in signal transduction pathways, are also of obvious importance in a neural context. Misregulation of MMP activity is a hallmark of many neuropathologies, and members of every branch of the MMP family have been implicated in aspects of neural development and disease. However, while extraordinary research efforts have been made to elucidate the molecular mechanisms involving MMPs, methodological constraints and complexities of the research models have impeded progress. Here we discuss the current state of our understanding of the roles of MMPs in neural development using recent examples and advocate a phylogenetically diverse approach to MMP research as a means to both circumvent the challenges associated with specific model organisms, and to provide a broader evolutionary context from which to synthesize an understanding of the underlying biology.

Experimental Dissection of Metalloproteinase Inhibition-Mediated and Toxic Effects of Phenanthroline on Zebrafish Development

“…Most of what we know about metalloproteinases is based on in vitro studies. The complexity of metalloproteinase regulation, and limitations of popular vertebrate model systems have made in vivo work especially difficult, and yet all the more important, as it is becoming increasingly clear that the tissue context in which these proteases function has enormous importance [ 11 , 12 ]. The zebrafish, long favored by developmental biologists and aquatic toxicologists, has emerged as a powerful vertebrate model in which to study the regulation of these proteases in vivo [ 13 ].…”

Matrix Metalloproteinase 13 Activity is Required for Normal and Hypoxia-Induced Precocious Hatching in Zebrafish Embryos

“…Inhibitor docking models comparing binding affinity indicate that the Mmp13PI will specifically target and inhibit zebrafish Mmp13a at concentration orders of magnitude lower than effective concentrations for inhibiting other proteases such as the HE itself [50], and targeted inhibition of Mmp13a activity dramatically inhibits hatching. Pharmacological MMP inhibitors have been studied extensively as potential drugs targeting cancer metastasis [54] and other disease pathologies [55,56], but limited progress using broad-spectrum inhibitors has both emphasized the importance of nuance in MMP biology and driven the development of highly-specific inhibitors to target individual MMPs. Despite the fact that this molecule was developed to target human MMP-13 rather than zebrafish Mmp13a, it has been successfully used experimentally in zebrafish [39,57] and qualitatively produces phenotypic effects analogous to effects observed in mammals.…”

The Kohlschütter-Tönz syndrome associated gene Rogdi encodes a novel presynaptic protein

“…In their secretory phase, ameloblasts secrete matrix metalloproteinases to promote enamel formation 31 , which is impaired in Kohlschütter-Tönz syndrome, leading to the clinical manifestation of amelogenesis imperfecta. Matrix metalloproteinases are also regulators of neuronal development 32 . In addition, ameloblasts express N-Cadherin, a transmembrane cell adhesion molecule crucial for brain development and synapse function 33 .…”