Neural Development of the Neuregulin Receptor ErbB4 in the Cerebral Cortex and the Hippocampus: Preferential Expression by Interneurons Tangentially Migrating from the Ganglionic Eminences

0 Oxford University Press 2003. All rights reserved 1 Department of Neuropharmacology, Scripps Research Institute , La Jolla, CA 92037, USA 2 Institute of Neuroscience, National Yang-Ming University , Taipei, Taiwan 112 , Republic of China The receptor tyrosine kinases represent an important class of signal transduction molecules that have been shown to play critical roles in neural development. We report in the present study that the neuregulin receptor ErbB4 is preferentially expressed by interneurons that are migrating tangentially from the ventral to the dorsal rat telencephalon. ErbB4 immunoreactivity was detected in the medial ganglionic eminence as early as embryonic day (E) 13 at the inception of tangential migration. Prominent ErbB4-positive migratory streams consisting of cells double-labeled with ErbB4 and Dlx, a marker of tangentially migrating cells, were found to advance along the lower intermediate zone and the marginal zone from the ventrolateral to the dorsomedial cortex at E16-E18. After E20, the ErbB4-positive stream in the lower intermediate zone shifted towards the germinal zone and further extended via the cortex into the hippocampal primordium. ErbB4 was not expressed by Tbr1-positive glutamatergic projection neurons during development. ErbB4 was preferentially expressed by the majority of parvalbuminpositive interneurons and subsets of other GABAergic interneurons in the cerebral cortex and the hippocampus in adulthood. The early onset and preferential expression of ErbB4 in tangentially migrating interneurons suggests that neuregulin/ErbB4 signaling may regulate the development and function of telencephalic interneurons. Introduction GABAergic inhibitory interneurons play important roles in the control of neural activity in the cerebral cortex. The modulation of neural circuits by interneurons is essential to the proper functioning of the cerebral cortex (McBain and Fisahn, 2001). Cortical interneurons comprise a heterogeneous neuronal population with different neurochemical and physiological properties. Cortical GABAergic interneurons express different calcium-binding proteins, including calbindin, parvalbumin and calretinin. They may also express different neuropeptides and neuromodulators, including somatostatin, vasoactive intestinal peptide and neuronal nitric oxide synthase (nNOS) (Cauli et al., 1997; Kawaguchi and Kubota, 1997; Benes and Berretta, 2001; McBain and Fisahn, 2001). A detailed classification based on morphological, electrophysiological and synaptic organization further suggests that cortical GA BAergic interneurons comprise highly heterogeneous populations (Gupta et al., 2000). Regarding the origins of cortical interneurons during development, evidence suggests that in rodent brains, most, if not all, cortical interneurons originate from the ventral telencephalon during development (Parnavelas, 2000; Corbin et al., 2001; Marin and Rubenstein, 2001; Nadarajah and Parnavelas, 2002). However, a distinct population of GA BAergic interneurons has recently been identified to originate from the developing dorsal telencephalon in humans (Letinic et al., 2002). Nonetheless, it remains largely unknown how GA BAergic interneurons are guided to the dorsal telencephalon during their long-distance migration from the ventral telencephalon and how different subtypes of interneurons are specified during development. The epidermal growth factor (EGF) receptor family consists of four receptor tyrosine kinases, including the EGF receptors ErbB1, ErbB2, ErbB3 and ErbB4 (Burden and Yarden, 1997; Gassmann and Lemke, 1997; Adlkofer and Lai, 2000; Garratt et al., 2000; Buonanno and Fischbach, 2001). The neuregulins (NRGs 14) have been identified as a family of EGF-domaincontaining molecules that serve as ligands for the ErbBs (Holmes et al., 1992; Peles et al., 1992; Wen et al., 1992; Falls et al., 1993; Marchionni et al., 1993; Busfield et al., 1997; Carraway et al., 1997; Chang et al., 1997; Zhang et al., 1997; Harari et al., 1999). Activation of ErbB receptors through tyrosine phosphorylation has been shown to regulate cell proliferation, migration and differentiation in different neural systems (Burden and Yarden, 1997; Adlkofer and Lai, 2000; Buonanno and Fischbach, 2001). For example, NRG-1 is a potent mitogen and survival factor for Schwann cells and is also capable of inducing acetylcholine receptor synthesis at the neuromuscular junction. NRG-1mediated ErbB2 and ErbB4 activation promotes the neuronprimed elongation of radial glia and neuronal migration in the cerebellum and cerebral cortex during development (Anton et al., 1997; Rio et al., 1997). Unlike ErbB2 and ErbB3, which appear to require heterodimerization for functional activation, ligand-induced homodimerization of ErbB4 is functionally competent in transducing NRG signals, which suggests that expression of ErbB4 by itself in neurons may be of functional significance (Plowman et al., 1993). An understanding of the (...truncated)