Specification of Distinct Dopaminergic Neural Pathways: Roles of the Eph Family Receptor EphB1 and Ligand Ephrin-B2

Abstract

Dopaminergic neurons in the substantia nigra and ventral tegmental area project to the caudate putamen and nucleus accumbens/olfactory tubercle, respectively, constituting mesostriatal and mesolimbic pathways. The molecular signals that confer target specificity of different dopaminergic neurons are not known. We now report that EphB1 and ephrin-B2, a receptor and ligand of the Eph family, are candidate guidance molecules for the development of these distinct pathways. EphB1 and ephrin-B2 are expressed in complementary patterns in the midbrain dopaminergic neurons and their targets, and the ligand specifically inhibits the growth of neurites and induces the cell loss of substantia nigra, but not ventral tegmental, dopaminergic neurons. These studies suggest that the ligand-receptor pair may contribute to the establishment of distinct neural pathways by selectively inhibiting the neurite outgrowth and cell survival of mistargeted neurons. In addition, we show that ephrin-B2 expression is upregulated by cocaine and amphetamine in adult mice, suggesting that ephrin-B2/EphB1 interaction may play a role in drug-induced plasticity in adults as well.

Regulation of netrin-1 receptors by amphetamine in the adult brain

“…These findings are in agreement with the recent observation that repeated pretreatment with stimulant drugs during adulthood regulates gene expression of a wide variety of guidance molecules (Bahi and Dreyer, 2005;Yue et al, 1999). We have also shown here that the effects of repeated AMPH on netrin-1 receptor expression are mediated by NMDA receptor activation, suggesting that netrin-1 signaling may play a role in the development of AMPH-induced sensitization.…”

“…Another possibility is that AMPH does induce changes in NAcc netrin-1 receptor expression, but that these changes only become evident at a later time point. Moreover, it may also be the case that guidance cues other than netrin-1 are involved in AMPH-induced alterations in neuronal structure in this terminal region (Yue et al, 1999). In contrast to the lack of effects of AMPH on netrin-1 receptor expression in the NAcc, we observed an increase in mPFC UNC-5 expression in AMPH-pretreated animals administered an AMPH challenge on the sensitization test day, compared with saline-pretreated controls.…”

Molecular basis for catecholaminergic neuron diversity

“…During development, SN neurons target mainly the dorsolateral striatum, whereas VTA neurons mainly innervate the ventromedial striatum. The molecular signals that regulate the development of these pathways have been characterized only partially (47). The differential expression of multiple members of the ephrin͞Eph and slit͞robo families identified here could have important functions in the maintenance and stability of neuronal networks, in adult plasticity and remodeling, and possibly in schizophrenia, a disease that is most likely linked to abnormal development of cortical areas innervated by VTA neurons (48).…”

Effects of overexpression of ephrin-B2 on tumour growth in human colorectal cancer

“…Northern blot analysis was performed as previously described (Ellis et al, 1996). After prehybridisation, the membranes were probed for ephrin-B2 full-length cDNA (the probe was a generous gift from Dr Renping Zhou, Laboratory for Cancer Research, College of Pharmacy, Rutgers University, Piscataway, NJ, USA; Yue et al, 1999), EphB4 (the probe was a purified polymerase chain reaction product with the primer sequences as follows: forward, 5 0 -GTCTGACTTTGGCCTTTCCC-3 0 ; reverse, 5 0 -TGACATCACCTCCCACATCA-3 0 ), and glyceraldehyde-phosphate dehydrogenase (internal control; ATCC). Each cDNA probe was purified by agarose gel electrophoresis, recovered by using a QIAEX gel extraction kit (QIAGEN Inc., Chatsworth, CA, USA), and radiolabelled by a random primer technique with a commercially available kit (Amersham Life Science Inc., Arlington Heights, IL, USA).…”