Multiple Eph Receptors and B-Class Ephrins Regulate Midline Crossing of Corpus Callosum Fibers in the Developing Mouse Forebrain

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.

A network of genetic repression and derepression specifies projection fates in the developing neocortex

“…Although the loss of single genes does not result in dramatic callosal abnormalities, double knockouts of various genotypes do compromise callosal development, suggesting that there is redundancy built into the system. Indeed, it is interesting to note that although restroring EphA4 expression in Satb2 mutants rescued callosal projections, EphA4 knockout mice fail to display callosal defects (28). However, multiple EphB receptors (B1, B2, and B3) and ligands (ephrinB1, B2, and B3) are expressed in callosal fibers and midline guidepost cells, respectively, and it is likely that their functions are redundant.…”

“…Prior studies have implicated Ephs and ephrins in callosal development (13,28,29). EphA4 is normally expressed in upper layer callosal neurons and the glial wedge (28). In Satb2 mutants, EphA4 expression is lost in cortical neurons, but expression in the glial wedge is maintained (9).…”

“…In particular, three axonal guidance molecules (EphA4, PlxnA4, and Unc5H3) are down-regulated in upper layers of mice lacking Satb2. Prior studies have implicated Ephs and ephrins in callosal development (13,28,29). EphA4 is normally expressed in upper layer callosal neurons and the glial wedge (28).…”

EphB receptor forward signaling regulates area-specific reciprocal thalamic and cortical axon pathfinding

“…EphB1 and EphB2 receptors are both expressed in the developing cortex (21,22). To test their role in cortical axon guidance, we assessed L1-cell adhesion molecule+ (L1-CAM + ) axons traversing the VTel in wild-type (WT), EphB1 −/− , EphB2 −/− , and EphB1/2 double knockout (DKO) (EphB1 −/− Significance In this study, we report a critical role of EphB forward signaling in proper thalamocortical axon guidance.…”

Truncated Cables1 causes agenesis of the corpus callosum in mice

“…Indeed, abnormal corpus callosum development has been reported in mice with deficiencies in these genes. [15][16][17][18][19][20][21][22] Occasionally, random integration of transgene DNA into the host genome disrupts an endogenous gene and causes a class of mutations called transgene insertion mutations. 23 Approximately 5-15% of random DNA insertion events in transgenic mice are associated with an abnormal phenotype by transgene insertion mutation.…”