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Corpus Callosum Deficiency in Transgenic Mice Expressing a Truncated Ephrin-A Receptor

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Corpus Callosum Deficiency in Transgenic Mice Expressing a Truncated Ephrin-A Receptor The Journal of Neuroscience, November 26, 2003 • 23(34):10963–10970 • 10963 Development/Plasticity/Repair Corpus Callosum Deficiency in Transgenic Mice Expressing a Truncated Ephrin-A Receptor Zhaoliang Hu,1,3 Xin Yue,1,3 Guanfang Shi,1,3 Yong Yue,1,3 David P. Crockett,3 Jan Blair-Flynn,4 Kenneth Reuhl,2 Lino Tessarollo,4 and Renping Zhou1,3 1Laboratory for Cancer Research and 2Department of Pharmacology, College of Pharmacy, Rutgers University, and 3Department of Neuroscience and Cell Biology, Robert Wood Johnson Medical School, Piscataway, New Jersey 08854, and 4Neural Development Group, Mouse Cancer Genetics Program, National Cancer Institute–Frederick Cancer Research and Development Center, Frederick, Maryland 21701 The A-class of the erythropoietin-producing hepatocellular carcinoma cell-derived (EphA) tyrosine kinase receptors and their ligands, the A-ephrins, play critical roles in the specification of topographic axon projection maps during development. In this study, the role of the EphA subfamily in callosal projections was investigated using transgenic mice expressing a kinase deletion mutant of EphA5. In approximately half of these transgenic mice, cerebral cortical neurons in various cortical regions (primary and secondary somatosensory cortices and frontal as well as visual areas) failed to project to the contralateral cortex. When commissural axons were examined with DiI labeling, few callosal fibers were found to traverse the midline in both the adult and neonatal transgenic mice. This defect in callosal development correlates with the expression of the transgene, because neurons in the superficial layers of the motor cortex, where transgene expression is low, show normal contralateral projection through the corpus callosum. In addition, multiple EphA receptors are expressed in callosal neurons and ephrin-A5 stimulates neurite outgrowth of callosal neurons in vitro. The midline glia structures important for callosal axon midline crossing appear normal in the transgenic mice, suggesting that the defects are unrelated to defective guidance structures at the midline. These observations suggest critical functions for EphA receptor in establishing callosal connections during brain development. Key words: corpus callosum; axon guidance; Eph receptors; ephrins; transgenic mice; neurite outgrowth Introduction tions, a number of decisions have to be made by the axons. In the Contralateral cerebral cortical projections through the corpus mouse, callosal axons must first find their way to the cortical callosum integrate sensory and motor performance of the two white matter and then turn medially, cross the midline, and then brain hemispheres. In “split-brain” animals and individuals reenter appropriate contralateral cortical areas to form synapses whose corpus callosum have been severed, interhemispheric with the target neurons. Disruptions at any of these critical choice transfer of sensory and motor information is deficient (Gazza- points will likely lead to pathfinding and targeting errors. niga, 1995). In these individuals, visual and tactile information Although the corpus callosum is critical for information presented to one hemisphere is not available for analysis by the transfer between the two hemispheres, the mechanisms guiding other hemisphere. In addition, perceptual interactions between the development of this fiber system are not well understood. the two hemispheres are absent in these individuals. These obser- Previously it has been shown that the erythropoietin-producing vations, pioneered by Roger Sperry in the 1960s (Sperry, 1968, hepatocellular carcinoma cell-derived A5 (EphA5), a member of 1982), defined the critical roles of contralateral cortical projec- the large Eph family of tyrosine kinase receptors, is expressed in tions in human consciousness and behavior. the cortical layers 2/3 and 5 (Zhang et al., 1997), where most of Anatomical studies in a wide variety of animals revealed that a the callosal neurons reside. The expression of EphA5 in these large proportion of the contralateral projection (callosal) neu- cortical layers raises the possibility that EphA receptors may func- rons are located in layers 2/3 and 5 (Innocenti, 1984). Callosal tion to guide callosal axons, because a prominent function of the axons project mostly to corresponding, homotopic areas of the Eph family is axon guidance (Flanagan and Vanderhaeghen, contralateral cortex. During the development of callosal projec- 1998; Zhou, 1998; Dodelet and Pasquale, 2000; Wilkinson, 2000; Kullander and Klein, 2002). Consistent with this notion, EphB2 and EphB3 have been shown previously to be important for the Received Aug. 20, 2003; revised Sept. 26, 2003; accepted Sept. 26, 2003. This research was supported in part by grants from the National Institutes of Health, the National Science development of the anterior commissure and the corpus callo- Foundation, and the New Jersey Governor’s Council on autism to R.Z. We thank M. David Egger and Ping Chao for sum (Henkemeyer et al., 1996; Orioli et al., 1996). To determine assistance in imaging and statistical analysis, and Linda Richards for critical comments on this manuscript. whether EphA receptors also contribute to the development of Correspondence should be addressed to Dr. Renping Zhou, Laboratory for Cancer Research, College of Pharmacy, the corpus callosum, we examined transgenic mice carrying a Rutgers University, Piscataway, NJ 08854. E-mail: [email protected]. Ϫ Y. Yue’s present address: CNS Disease Department, Aventis Pharmaceuticals, Bridgewater, NJ 08807. mutated form of the receptor EphA5, EphA5(K ), generated Copyright © 2003 Society for Neuroscience 0270-6474/03/2310963-08$15.00/0 previously (Yue et al., 2002). The mutant receptor contains the 10964 • J. Neurosci., November 26, 2003 • 23(34):10963–10970 Hu et al. • Regulation of Callosal Projections by EphA Receptors ligand-binding and transmembrane domains of EphA5, but the containing 30% sucrose at 37°C, brain sections of 100 ␮m thickness were intracellular kinase domain has been replaced with an enhanced cut with a vibratome and examined with a Zeiss Axioskope equipped green fluorescence protein (eGFP). This truncated receptor in- with Fluoro-Gold or rhodamine filters. Quantification of retrogradely hibits the activity of the wild-type EphA receptors and therefore labeled callosal neurons was performed in control and in phenotypically interferes with the function of the endogenous EphA receptors positive brain sections only. Glial fibrillary acidic protein immunocytochemistry. The newborn (Yue et al., 2002). In EphA5(K-) transgenic mice, medial hip- [postnatal day (P) 0] animals were anesthetized by cooling on ice over a pocampal axons terminate more ventrally compared with the metal plate, perfused with 4% PFA in 0.5ϫ PBS, and postfixed in PFA for wild type, indicating a critical function of the EphA receptors and 2–4 hr. Postfixed brains were cryoprotected in 30% sucrose overnight ligands in topographic mapping of hippocampal axon terminals and sectioned with a cryostat. After preincubation with PBS containing (Yue et al., 2002). Here we report that in approximately half of 2% normal goat serum and 0.25% BSA for 1 hr, the tissue sections were these mice, the contralateral cerebral cortical projection is also incubated with rabbit anti-cow glial fibrillary acidic protein (GFAP) an- deficient. Callosal axons show reduced growth toward the callosal tibody (1:1000, Dako, Glostrup, Denmark; product code Z0334) fol- axon tract and the midline, revealing a new function of the EphA lowed by Cy3-conjugated goat anti-rabbit antibody (Jackson Immu- receptors in the development of axon pathways. noResearch, West Grove, PA; 1 ␮g/ml). Double labeling of callosal neurons with Fluoro-Gold retrograde tracing Materials and Methods and anti-EphA receptor antibodies in early postnatal mice. The P0 animals Transgenic mice. EphA5(K-) transgenic mice were generated in C57BL/6J were anesthetized by cooling on ice over a metal plate; Fluoro-Gold (0.5 X C3H/HeJ F1 background as described previously (Yue et al., 2002). ␮l) was injected into the somatosensory cortex unilaterally. After2dof These mice express a truncated EphA5 receptor [EphA5(K-)] fused to survival, the labeled pups were perfused with 4% paraformaldehyde in eGFP under the transcriptional control of a neuron-specific ␣-tubulin 0.05 M PBS and postfixed in the same fixative for 2–4 hr. Postfixed brains promoter. The transgene retains the extracellular and transmembrane were kept in 30% sucrose overnight and sectioned with a cryostat. Pre- domains but lacks the intracellular domain of EphA5 receptor. Two in- incubation was performed as described in the previous section. The tis- dependent lines of mice (Ag30–61 and Ag0072) were analyzed, and both sue sections were then incubated with rabbit anti-EphA3 (c-19) and yielded similar results. Mice with higher copy numbers of the transgene -EphA7 (k-16) antibodies (Santa Cruz Biotechnology, Santa Cruz, CA; 1 were identified using PCR as well as Southern blot analysis as described ␮g/ml) or human ephrin-A5/crystallizable fragment of IgG (Fc) chimera (Yue et al., 2002). Two different controls have been used in this analysis: diluted in 0.5ϫ PBS (0.5 ␮g/ml;R&DSystems, Minneapolis, MN) at 4°C (1) wild-type nontransgenic (C57BL/6J X C3H/HeJ) F1 mice bred in overnight. After three washes of 15 min each with 0.5ϫ PBS, the sections parallel to the transgenic animals and (2) transgenic mice expressing only were incubated with biotinylated
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