Domain-specific olivocerebellar projection regulated by the EphA-ephrin-A interaction

Abstract

Neural maps in the vertebrate central nervous system often show discontinuously segregated, domain-to-domain patterns. However, the molecular mechanism that establishes such maps is not well understood. Here we show that in the chicken olivocerebellar system, EphA receptors and ephrin-As are expressed with distinct levels and combinations in mapping domains. When ephrin-A2 is retrovirally overexpressed in the cerebellum, the olivocerebellar map is disrupted, excluding axons with high receptor activity from ectopic expression domains. Conversely, overexpression of a truncated EphA3 receptor in the cerebellum reduces endogenous ligand activity to undetectable levels and causes aberrant mapping, with high receptor axons invading high ligand domains. In vitro, ephrin-A2 inhibits outgrowth of inferior olive axons in a region-specific manner. These results suggest that Eph receptors and ephrins constitute domain-specific positional information, and the spatially accurate receptor-ligand interaction is essential to guide inferior olive axons to their correct target domains.

Schizophrenia-Related Neural and Behavioral Phenotypes in Transgenic Mice Expressing TruncatedDisc1

“…The probe for the transgene expression was reversely transcribed from the entire EGFP coding sequence. The hybridization was performed as described (Nishida et al, 2002).…”

Loss-of-Function Analysis of EphA Receptors in Retinotectal Mapping

“…RCAS-EphA3⌬C has been described (Nishida et al, 2002). Titers of the retrovirus stocks used in the present studies were 1-5 ϫ 10 8 ml Ϫ1 for RCAS-EphA3⌬C.…”

“…Here, we tested the effect of a truncated EphA3 receptor, using the virus RCAS-EphA3⌬C. This vector encodes an EphA3 receptor lacking most of the intracellular region, including the tyrosine kinase domain (Nishida et al, 2002). Such truncated receptors are expected to act in a dominant-negative manner by heterodimerizing with endogenous receptors or by sequestering ligand, and although the specific mechanism was not tested here, this approach has been used widely for Eph receptors and other receptor tyrosine kinases (van der Geer et al, 1994;Xu et al, 1995;Lackmann et al, 1998;Holmberg et al, 2000).…”

Molecular Mechanisms Controlling Midline Crossing by Precerebellar Neurons

“…DAO neurons are born first and are also the ones that are the most affected in Slit/Robo mutants. Before IO subdivisions adopt their final morphology, they already express different combination of proteins (Wassef et al, 1992), including axon guidance molecules and receptors (Chedotal et al, 1996;Nishida et al, 2002;Backer et al, 2007). Interestingly, mice lacking the Rho-GEF (guanine exchange factor) Trio exhibit IO lamellation defects resembling those observed in Robo1/Robo2 and Slit1/Slit2 mutants (Backer et al, 2007).…”