Pivotal Role of Early B-Cell Factor 1 in Development of Striatonigral Medium Spiny Neurons in the Matrix Compartment Mary Kay Lobo, 1,2,3 Christopher Yeh, 1,2,3 and X. William Yang 1,2,3 * 1 Center for Neurobehavioral Genetics, Semel Institute for Neuroscience, Brain Research Institute, University of California, Los Angeles, California 2 Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California 3 Brain Research Institute, University of California at Los Angeles, Los Angeles, California The mammalian striatum plays a critical function in motor control, motor and reward learning, and cogni- tion. Dysfunction and degeneration of the striatal neu- rons are implicated in major neurological and psychiat- ric disorders. The vast majority of striatal neurons are medium spiny neurons (MSNs). MSNs can be further subdivided into distinct subtypes based on their physi- cal localization in the striatal patch vs. matrix compart- ments and based on their axonal projections and marker gene expression (i.e., striatonigral MSNs vs. striatopallidal MSNs). Despite our extensive knowledge on the striatal cytoarchitecture and circuitry, little is known about the molecular mechanisms controlling the development of the MSN subtypes in the striatum. Early B-cell factor 1 (Ebf1) is a critical transcription fac- tor implicated in striatal MSN development. One study shows that Ebf1 is critical for the differentiation of MSNs in the matrix, and our separate study demon- strates that Ebf1 is selectively expressed in the striato- nigral MSNs and is essential for their postnatal differen- tiation. In the present study, we further validate the striatonigral MSN deficits in Ebf1 2/2 mice using multi- ple striatonigral MSN reporter mice. Moreover, we dem- onstrate that the striatonigral MSN deficits in these mice are restricted to those in the matrix, with relative sparing of those in the patch. Finally, we demonstrate that Ebf1 deficiency also results in reduced expression of another striatonigral-specific transcription factor, zinc finger binding protein 521 (Zfp521), which is a known Ebf1 functional partner. Overall, our study reveals that Ebf1 may play an essential role in controlling the differ- entiation of the striatonigral MSNs in the matrix compartment. V V C 2008 Wiley-Liss, Inc. Key words: striatum; transcription factors; striatal neurons; knockout mouse; development The striatum (made up of caudate and putamen nuclei in humans) is the largest nucleus in the basal gan- glia (BG), and it integrates the afferent inputs from the cortex, thalamus, and substantia nigra. The principal pro- jection neurons in the striatum are the medium spiny neurons (MSNs), which constitute 90–95% of all the neurons in the striatum (Gerfen, 1992; Nakano et al., 2000). MSNs are divided into two morphologically identical and mosaically distributed projection neuron pathways: striatonigral neurons (the direct pathway), which project to globus pallidus interna (GPi) and sub- stantia nigra (SN), and striatopallidal neurons (indirect pathway), which project to globus pallidus externa (Gpe; Fig. 1a), which indirectly influence the SN via the sub- thalamic nucleus (STN; Gerfen, 1992). Current models of BG function (Albin et al., 1989; Graybiel, 2000; DeLong and Wichmann, 2007) suggest that the two striatal projection neuron pathways provide balanced, but antagonistic, influences on the BG output and behavior. Despite insights into the disparate functional roles of the two MSNs, the differential developmental processes in these neuronal subtypes are poorly under- stood. The striatum can be further subdivided into multi- ple compartments. One such level of compartmentaliza- tion is the separation into dorsal and ventral striatum, the latter comprising nucleus accumbens (NAc) shell and core (Fig. 1a,b). The dorsal striatum is well known to play a role in motor behaviors (Albin et al., 1989; DeLong and Wichmann, 2007), and ventral striatum is known for its role in emotional and reward behaviors (Cardinal et al., 2002; Pecina et al., 2006). Another level Contract grant sponsor: UCLA Hatos Center grant from NIDA; Contract grant number: 2P50DA005010 (to X.W.Y.); Contract grant sponsor: UCLA MRRC training grant from NICHD; Contract grant number: 5T32HD007032 (to M.K.L.). *Correspondence to: X. William Yang, Center for Neurobehavioral Genetics, Semel Institute for Neuroscience, Brain Research Institute, University of California, 695 Charles Young Drive South, Los Angeles, CA 90095. E-mail: xwyang@mednet.ucla.edu Received 18 September 2007; Revised 21 December 2007; Accepted 21 December 2007 Published online 13 March 2008 in Wiley InterScience (www. interscience.wiley.com). DOI: 10.1002/jnr.21666 Journal of Neuroscience Research 86:2134–2146 (2008) ' 2008 Wiley-Liss, Inc.