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Assaying the Ability of Diffusible Signaling Molecules to Reorient Embryonic Spinal Commissural Axons
Published on: March 8, 2010
miR-219a-Robo1 axis acts as a conserved switch for slit-mediated commissural axon guidance
Bhakti Khot1, Harindi Suriyaarachchi1, Tanushree Majumder1
1Department of Molecular, Cellular, and Developmental Biology, College of Natural Sciences and Mathematics, University of Toledo, M.S. 601, 2801 W. Bancroft St., Toledo, OH 43606, USA.
Abstract:
Vertebrate commissural axon (CA) projection and midline crossing require suppression of Slit responsiveness in precrossing axons and its upregulation in postcrossing axons. Differential expression of the Slit receptor Robo1-low in precrossing and high in postcrossing axons-modulates Slit sensitivity and regulates midline crossing. However, the underlying mechanisms controlling this remain unclear. This study demonstrates that the 3' untranslated region (UTR) of Robo1 mRNA is regulated by the conserved miR-219a. In the developing spinal cord, gga-miR-219a and cRobo1 exhibit distinct, trajectory-specific expression patterns. miR-219a suppresses cRobo1 protein translation in commissural neurons (CNs) without affecting mRNA levels. Disruption of the miR-219a-cRobo1 3' UTR axis in precrossing CNs triggers premature Slit repulsion in vitro and causes spinal CA defects in vivo. Conditional knockout of mmu-miR-219a in E11.5 mouse embryos elevates mRobo1 protein and causes CA guidance defects. These findings reveal a conserved miR-219a-dependent mechanism that regulates Robo1 expression and Slit-mediated axon guidance.
Insights
MicroRNA miR-219a regulates Robo1 expression in developing neurons, controlling axon guidance. This finding reveals a conserved mechanism essential for proper spinal cord wiring and midline crossing in vertebrates.
Area of Science:
- Neuroscience
- Developmental Biology
- Molecular Biology
Background:
- Axon guidance is crucial for neural circuit formation.
- Slit-Robo signaling regulates commissural axon midline crossing.
- Differential expression of Robo1 impacts Slit sensitivity, but regulatory mechanisms are unclear.
Purpose of the Study:
- To investigate the regulatory mechanisms controlling Robo1 expression during axon guidance.
- To determine the role of miR-219a in modulating Slit responsiveness in commissural neurons.
Main Methods:
- Analysis of miR-219a and Robo1 expression patterns in developing spinal cords.
- In vitro studies using commissural neurons to assess Slit repulsion.
- In vivo experiments involving conditional knockout of miR-219a in mouse embryos.
Main Results:
- miR-219a directly targets the 3' UTR of Robo1 mRNA, suppressing protein translation.
- Disruption of the miR-219a-Robo1 axis leads to premature Slit repulsion and axon guidance defects.
- Conditional knockout of miR-219a results in elevated Robo1 protein and impaired commissural axon projection.
Conclusions:
- A conserved miR-219a-dependent mechanism regulates Robo1 expression.
- This regulation is critical for controlling Slit-mediated axon guidance and midline crossing.
- The findings elucidate a novel pathway in neural development and wiring.
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