Abstract
Retinal axon specification and growth are critically sensitive to the dosage of numerous signaling molecules and transcription factors. Subtle variations in the expression levels of key molecules may result in a variety of axonal growth anomalies. miR-181a and miR-181b are two eye-enriched microRNAs whose inactivation in medaka fish leads to alterations of the proper establishment of connectivity and function in the visual system. miR-181a/b are fundamental regulators of MAPK signaling and their role in retinal axon growth and specification is just beginning to be elucidated. Here we demonstrate that miR-181a/b are key nodes in the interplay between TGF-β and MAPK/ERK within the functional pathways that control retinal axon specification and growth. Using a variety of in vivo and in vitro approaches in medaka fish, we demonstrate that TGF-β signaling controls the miR-181/ERK regulatory network, which in turn strengthens the TGF-β-mediated regulation of RhoA degradation. Significantly, these data uncover the role of TGF-β signaling in vivo, for the first time, in defining the correct wiring and assembly of functional retina neural circuits and further highlight miR-181a/b as key factors in axon specification and growth.
Highlights
Eye formation in vertebrates requires a series of morphogenetic events orchestrated by the interplay between a number of signaling pathways and transcription factors that regulate specific genetic programs
We hypothesize that miR-181a/b may act as nodes in a signaling network involving transforming growth factor-β (TGF-β) and MAPK/ERK pathways
The negative modulation exerted by the miR-181/ERK pathway on Cofilin/ADF (Actin Depolarization Factor) and RhoA protein synthesis is necessary for proper neuritogenesis in both amacrine cells and retinal ganglion cells (RGCs) via local cytoskeletal rearrangement [14]
Summary
Eye formation in vertebrates requires a series of morphogenetic events orchestrated by the interplay between a number of signaling pathways and transcription factors that regulate specific genetic programs. The present study aims at elucidating whether TGF-β may control the MAPK/ERK pathway in the process of retinal axon specification and growth in vivo and whether this action could be mediated through the modulation of miR-181a/b expression. To reach this goal, we relied on the medaka fish [Oryzias latipes (Ol)] model organism whose genome harbors four different copies of the miR-181a/b clusters, namely on chromosome 4, chromosome 9, chromosome 17 and on a locus that is yet unassigned (Ultracontig105) [14]. This study is the first to reveal in vivo that miR-181a/b are part of the TGF-β genetic network, adding knowledge to the repertoire of TGF-β activities during the course of axon specification and growth in vertebrate eye development
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