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Multiple Eph receptors and B-class ephrins regulate midline crossing of corpus callosum fibers in the developing
Shannon W Mendes1, Mark Henkemeyer, Daniel J Liebl
1Neuroscience Program, University of Miami Miller School of Medicine, Miami, Florida 33136, USA.
Abstract:
Agenesis of the corpus callosum (CC) is a rare birth defect that occurs in isolated conditions and in combination with other developmental cerebral abnormalities. Recent identification of families of growth and guidance molecules has generated interest in the mechanisms that regulate callosal growth. One family, ephrins and Eph receptors, has been implicated in mediating midline pathfinding decisions; however, the complexity of these interactions has yet to be unraveled. Our studies shed light on which B-class ephrins and Eph receptors function to regulate CC midline growth and how these molecules interact with important guideposts during development. We show that multiple Eph receptors (B1, B2, B3, and A4) and B-class ephrins (B1, B2, and B3) are present and function in developing forebrain callosal fibers based on both spatial and temporal expression patterns and analysis of gene-targeted knock-out mice. Defects are most pronounced in the combination double knock-out mice, suggesting that compensatory mechanisms exist for several of these family members. Furthermore, these CC defects range from mild hypoplasia to complete agenesis and Probst's bundle formation. Further analysis revealed that Probst's bundle formation may reflect aberrant glial formations and/or altered sensitivity of CC axons to other guidance cues. Our results support a significant role for ephrins and Eph receptors in CC development and may provide insight to possible mechanisms involved in axon midline crossing and human disorder.
Insights
Ephrins and Eph receptors are crucial for corpus callosum (CC) development, guiding forebrain callosal fibers. Their complex interactions and compensatory roles influence CC formation, with defects leading to agenesis or Probst's bundles.
Area of Science:
- Neuroscience
- Developmental Biology
- Genetics
Background:
- Agenesis of the corpus callosum (CC) is a rare birth defect impacting brain development.
- Understanding the molecular mechanisms regulating CC formation is crucial for addressing related disorders.
- Ephrin and Eph receptor signaling pathways are implicated in neural development and guidance.
Purpose of the Study:
- To investigate the specific roles of B-class ephrins and Eph receptors in corpus callosum development.
- To elucidate how these molecules interact with developmental guideposts during forebrain development.
- To understand the genetic basis of CC agenesis and related malformations.
Main Methods:
- Analysis of spatial and temporal expression patterns of Eph receptors (B1, B2, B3, A4) and B-class ephrins (B1, B2, B3) in developing forebrain callosal fibers.
- Utilizing gene-targeted knock-out mouse models, including combination double knock-outs.
- Investigating Probst's bundle formation and potential glial abnormalities.
Main Results:
- Multiple Eph receptors and B-class ephrins are expressed and functional in developing callosal fibers.
- Gene knock-out studies revealed significant CC defects, most pronounced in double knock-outs, indicating functional redundancy.
- Observed CC defects ranged from hypoplasia to agenesis, including Probst's bundle formation, potentially linked to glial aberrations.
Conclusions:
- Ephrin and Eph receptor signaling plays a significant role in corpus callosum development and axon midline crossing.
- Compensatory mechanisms exist among these signaling molecules, influencing the severity of CC defects.
- Findings offer insights into the molecular basis of CC agenesis and related human disorders.
