Title: Matrix metalloproteinase 14 in the zebrafish: an eye on retinal and retinotectal development
Other Titles: Matrix metalloproteïnase 14 in de zebrafish: een blik op de retinale en retinotectale ontwikkeling
Authors: Janssens, Els
Issue Date: 26-Nov-2012
Abstract: Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases and belong to a larger family of metzincin peptidases. They are mainly known for their capacity to cleave structural elements of the extracellular matrix and to (in)activate many molecules involved in signal transduction. As a result, they are involved in a wide variety of biological processes. Besides a proven detrimental role in neurological diseases, a beneficial role for MMPs in key physiological and regenerative brain events is emerging, indicating these proteinases as relevant therapeutic targets in the pathological central nervous system (CNS). Importantly, MMPs not only affect migration and survival of neurons, axon guidance, myelination and synaptogenesis, they also appear to modulate neural stem cell properties and differentiation. Although an involvement of MMPs in the development and regeneration of the optic circuit was sporadically reported, the nature and working mechanisms of individual MMPs in retinal and retinotectal development are still to be elucidated.MMP14 is a membrane-bound MMP that is involved in mediating a wide range of processes. This protein is mostly known for its detrimental role in cancers, where MMP14 is responsible for cell migration, tumor invasion and angiogenesis, resulting in highly vascularized tumors, and thus a poor outcome for patients with high MMP14 expression in tumor cells. Furthermore, MMP14 is reported to be involved in blood-brain barrier disruption after cerebral ischemia or trauma and is also suggested to play a role in Parkinson¬ís disease. Besides these detrimental functions, MMP14 expression is crucial in bone development and has been found in the developing and adult mammalian eye. Within this study, we intended to unravel the role of zebrafish Mmp14a, one of the two isoforms of mammalian MMP14, during retinal and retinotectal axon pathfinding development. Since the zebrafish eye and visual system are easy to manipulate, fairly well characterized and highly conserved in vertebrates, it forms a powerful model system to study retinal and retinotectal pathway development.In the first part of our research, we showed, using whole mount in situ hybridization and immunohistochemistry, that Mmp14a expression can be found in the optic circuit of the developing zebrafish, such as the inner plexiform layer, the inner nuclear layer and the retinal ganglion cell layer of the retina, as well as in the optic nerve, the postoptic commissure and the neuropil of the optic tectum. Next, genetic inactivation of Mmp14a using morpholino technology resulted in microphthalmia, although it did not affect early eye development or general embryo morphology. By investigating the smaller eye phenotype in more detail, we identified a prolonged retinoblast proliferation, a retarded retinal neurogenesis wave, and a delayed retinal cell differentiation and retinal lamination in zebrafish embryos after Mmp14a knockdown. Moreover, Mmp14a morphants showed a persistently impaired innervation of the optic tectum. In contrast to Mmp14a, knockdown of Mmp14b did not result in any obvious defects in retinal neurogenesis or retinotectal pathway development.Finally, we also determined some of the mechanisms and possible substrates via which Mmp14a regulates retinal neurogenesis and retinotectal axon pathfinding. We elucidated a possible co-involvement of Mmp2 and Mmp14a and identified Laminin1 and Cadherin11 as possible Mmp14a substrates in retinal and retinotectal development. Furthermore, preliminary findings suggest a possible interaction of Shh and/or Fgf, two major extrinsic factors involved in retinal neurogenesis, with Mmp14a in proper optic circuit development.Altogether, these findings reveal a prominent and novel role for Mmp14a in the development of the neuroretina and the retinotectal pathway in zebra-fish and may therefore have implications for future strategies interfering with optic circuit development and/or regeneration.
Publication status: published
KU Leuven publication type: TH
Appears in Collections:Animal Physiology and Neurobiology Section - miscellaneous

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