Rapid Publication Patterning of the Lateral Ganglionic Eminence by the Gsh1 and Gsh2 Homeobox Genes Regulates Striatal and Olfactory Bulb Histogenesis and the Growth of Axons through the Basal Ganglia KYUSON YUN, SONIA GAREL, SETH FISCHMAN, AND JOHN L.R. RUBENSTEIN * Nina Ireland Laboratory of Developmental Neurobiology, Department of Psychiatry, LPPI, University of California at San Francisco, San Francisco, California 94143-0984 ABSTRACT The function of the Gsh1 and Gsh2 homeobox transcription factors during development of the mouse telencephalon was studied using loss of function mutations. No telencephalic pheno- type was observed in Gsh1 mutants, whereas Gsh2 and Gsh1/2 mutants showed progressively more severe defects in development of neurons derived from the lateral ganglionic eminence (LGE). These defects arise from abnormal dorsoventral specification of LGE progenitor cells. Mice lacking both Gsh1 and Gsh2 have severe hypoplasia of the striatum, olfactory tubercle, and interneurons that migrate from the dorsal LGE to the olfactory bulb. In addition, Gsh function is linked to the development of telencephalic dopaminergic neurons. These observations show that Gsh1 and Gsh2 have early roles in defining the identity of LGE progenitor cells. As a result of the basal ganglia defects in the Gsh1/2 mutants, there are pallial heterotopia near the cortical/ subcortical limit and defects in the pathfinding of corticofugal and thalamocortical fibers. These findings highlight the developmental interdependence of adjacent telencephalic structures. J. Comp. Neurol. 461:151–165, 2003. © 2003 Wiley-Liss, Inc. Indexing terms: Gsh1; Gsh2; telencephalon; dorsoventral patterning; LGE; ventral pallium; striatum; cortical axons; CNS development The subcortical telencephalon (subpallium) has major roles in regulating motor, cognitive, and emotional pro- cesses. This region consists primarily of the basal ganglia (striatum and pallidum) and parts of the amygdala and septum. These regions are derived, in large part, from distinct progenitor zones: lateral ganglionic eminence (LGE), medial ganglionic eminence (MGE), preoptic/ anterior entopeduncular (POA/AEP), septal and caudal ganglionic eminence (CGE), respectively. Each of these areas has a distinctive histology, and each is further sub- divided into nuclear and laminar components. For in- stance, major parts of the striatal territory include the caudate, putamen, accumbens, and olfactory tubercle (Heimer et al., 1995). Within the caudate and putamen, subsets of cells are organized into patches that are inter- calated between matrix cells (Gerfen, 1992; Graybiel, Grant sponsor: the Tourette’s Syndrome Foundation; Grant sponsor: Nina Ireland; Grant sponsor: National Institute on Drug Abuse; Grant number: R01DA12462; Grant sponsor: National Institutes of Mental Health; Grant number: K02 MH01046. *Correspondence to: John L.R. Rubenstein, Nina Ireland Laboratory of Developmental Neurobiology, Department of Psychiatry, LPPI, University of California, San Francisco, 401 Parnassus, Box 0984, San Francisco, CA 94143-0984. E-mail: jlrr@cgl.ucsf.edu Received 12 December 2002; Accepted 28 January 2003 DOI 10.1002/cne.10685 Published online the week of May 5, 2003 in Wiley InterScience (www. interscience.wiley.com). THE JOURNAL OF COMPARATIVE NEUROLOGY 461:151–165 (2003) © 2003 WILEY-LISS, INC.