The basal ganglia are known to regulate motor function and have recently been implicated in both social and cognitive functions as well. As a result, these brain nuclei have been implicated in childhood disorders, ADHD, OCD, Tourette's syndrome and autism, which display a spectrum of behavioral abnormalities. These childhood disorders have been proposed to result from abnormal development/function of basal ganglia circuitry. The striatum represents the major nucleus of the basal ganglia and the striatal projection neurons (SPNs) comprise the major neuronal subtype on which the basal ganglia circuit is dependent. The direct pathway (d)SPNs project to the output nuclei of the basal ganglia, while the indirect pathway (i)SPN axons innervate an intermediate nucleus and indirectly influencing the output nuclei though a polysynaptic circuit. Balanced activity between these two pathways is fundamental for normal brain function. Despite the importance of these striatal output pathways, little is known about the molecular genetic mechanisms controlling their formation. In the previous funding cycle, we showed that the transcription factor Isl1 is required for the normal formation of dSPNs. In its absence, these neurons are generated but do not survive and as a result, innervation of the output nuclei is severely compromised. Isl1 conditional mutants (cKOs) exhibit behavioral abnormalities reminiscent of ADHD as they are hyperactive and blunted to psychostimulant treatment. Moreover, we identified the transcription factor Sox8 in dSPNs. Our data indicate that the direct pathway axons do not project properly in Sox8 homozygous mutants. However, unlike the Isl1 cKOs, no SPN cell death was observed. Interestingly, Sox8 heterozygotes showed a partial phenotype with reduced direct pathway axonal innervation. Both the heterozygous and homozygous Sox8 animals exhibited hyperactivity, reminiscent of Isl1 cKOs, as well as, cognitive impairments. The main goal of this proposal is to understand the molecular genetic pathways controlling the development of dSPNs and specifically the roles of the transcription factors Sox8, Bach2 and Arx with respect to neuronal survival/differentiation and axon outgrowth. We will achieve this by testing the following hypotheses: 1) Sox8 regulates dSPN axon outgrowth downstream of Ebf1 by controlling the timing of maturation, 2) Isl1 regulates a Foxo/Bach2-mediated survival/differentiation pathway in developing dSPNs and 3) Arx is required for development of dSPNs and their altered development in Arx mutants accounts for certain behavioral defects observed in these mutants. Our approach will combine molecular and cellular analysis of genetic mouse mutants exhibiting defined alterations in dSPN connectivity and correlate this with specific behavioral abnormalities in motor and cognitive function. The genetic models in this proposal may inform human studies of ADHD, OCD, Tourette's as well as autism and intellectual disabilities.
The telencephalon is the region of the brain most associated with cognition and voluntary purposeful movements. The basal ganglia play a crucial role in regulating these brain activities and it is believed that abnormal development and/or function of basal ganglia nuclei leads to childhood brain disorders including ADHD, OCD, Tourette's syndrome as well as autism and intellectual disability. At present, we do not fully understand the genetic pathways and underlying molecular mechanisms involved in the development of basal ganglia circuitry. In this proposal, we will investigate a number of genetic mouse mutants for developmental control genes that display altered basal ganglia circuitry and establish the impact of the observed anatomical alterations on motor, social and cognitive brain function. Given the similarities between the mouse and human basal ganglia, we expect our findings to be highly relevant for a better understanding of the underlying abnormalities in the above-mentioned childhood brain disorders.
|Tinterri, Andrea; Menardy, Fabien; Diana, Marco A et al. (2018) Active intermixing of indirect and direct neurons builds the striatal mosaic. Nat Commun 9:4725|
|Merchan-Sala, Paloma; Nardini, Diana; Waclaw, Ronald R et al. (2017) Selective neuronal expression of the SoxE factor, Sox8, in direct pathway striatal projection neurons of the developing mouse brain. J Comp Neurol 525:2805-2819|
|Waclaw, R R; Ehrman, L A; Merchan-Sala, P et al. (2017) Foxo1 is a downstream effector of Isl1 in direct pathway striatal projection neuron development within the embryonic mouse telencephalon. Mol Cell Neurosci 80:44-51|
|Ehrman, Lisa A; Mu, Xiuqian; Waclaw, Ronald R et al. (2013) The LIM homeobox gene Isl1 is required for the correct development of the striatonigral pathway in the mouse. Proc Natl Acad Sci U S A 110:E4026-35|