Mmp25β facilitates elongation of sensory neurons during zebrafish development

Abstract

Matrix metalloproteinases (MMPs) are a large and complex family of zinc-dependent endoproteinases widely recognized for their roles in remodeling the extracellular matrix (ECM) during embryonic development, wound healing, and tissue homeostasis. Their misregulation is central to many pathologies, and they have therefore been the focus of biomedical research for decades. These proteases have also recently emerged as mediators of neural development and synaptic plasticity in vertebrates, however, understanding of the mechanistic basis of these roles and the molecular identities of the MMPs involved remains far from complete. We have identified a zebrafish orthologue of mmp25 (a.k.a. leukolysin; MT6-MMP), a membrane-type, furin-activated MMP associated with leukocytes and invasive carcinomas, but which we find is expressed by a subset of the sensory neurons during normal embryonic development. We detect high levels of Mmp25β expression in the trigeminal, craniofacial, and posterior lateral line ganglia in the hindbrain, and in Rohon-Beard cells in the dorsal neural tube during the first 48 h of embryonic development. Knockdown of Mmp25β expression with morpholino oligonucleotides results in larvae that are uncoordinated and insensitive to touch, and which exhibit defects in the development of sensory neural structures. Using in vivo zymography, we observe that Mmp25β morphant embryos show reduced Type IV collagen degradation in regions of the head traversed by elongating axons emanating from the trigeminal ganglion, suggesting that Mmp25β may play a pivotal role in mediating ECM remodeling in the vicinity of these elongating axons.

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

“…Pharmacological inhibition of MMP2 and 14 impaired melanophore migration in Xenopus [ 42 ], but broad spectrum metalloproteinase inhibitors did not affect neural crest migration in several other experiments [ 43 ]. Paradoxically, morpholino knockdown of Mmp17b alone significantly impairs neural crest migration in zebrafish [ 34 ] and knockdown of Mmp25a disrupts development of neural crest-derived neuromasts [ 44 ]. Furthermore, here we show that migration and/or survival of the neural-crest-derived cells of the craniofacial cartilages and otic vesicle is profoundly disrupted by PhN ( Figure 4 ).…”

The zebrafish as a promising tool for modeling human brain disorders: A review based upon an IBNS Symposium

“…However, screening natural products for specific biological properties is a daunting task, as one often has to start with a complex mixture of unknown compounds, a problem that may be resolved with purification. The combination of purification and zebrafish-based screening has already been successfully employed (Bohni et al, 2013;Brillatz et al 2016;Challal et al, 2014;Crawford et al, 2014;Tabassum et al, 2015).…”

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

“…Pharmacological inhibition of MMP2 and 14 impaired melanophore migration in Xenopus [42], but broad spectrum metalloproteinase inhibitors did not affect neural crest migration in several other experiments [43]. Paradoxically, morpholino knockdown of Mmp17b alone significantly impairs neural crest migration in zebrafish [34] and knockdown of Mmp25a disrupts development of neural crest-derived neuromasts [44]. Furthermore, here we show that migration and/or survival of the neural-crest-derived cells of the craniofacial cartilages and otic vesicle is profoundly disrupted by PhN (Fig.…”