(Sea instructions): Recent findings that white matter tracts, particularly the corpus callosum, show abnormal organization in autistic individuals have focused our interest on later steps of cortical maturation, and in particular on the ability of cortical neurons to extend axons to specific long distance targets. In previous work, my lab has worked on the roles of four key transcription factors?Fezf2. Ctip2, Tbr1 and Satb2?in specifying projection neuron fates. We showed that Satb2, a DNA-binding protein that regulates chromatin organization and gene expression, is expressed in cortical neurons that extend axons across the corpus callosum, and that Satb2 mutant neurons alter their projections and extend axons to subcortical structures. Conversely, Fezf2, Tbr1 and Ctip2 are expressed by neurons that form subcortical projects. In the presence of Fezf2, neurons adopt a subcortical projection neuron identity; in its absence, many layer 5 and 6 neurons become callosal projection neurons5. The fate change affects not only the projections of Fezf2-expressing cells but also their gene expression and electrophysiological properties, both of which acquire callosal characteristics. These and other experiments have fueled our current interest in the transcriptional networks that control projection neuron identity. Here we propose to extend this work into a new realm, by performing a genome-wide assessment of the transcriptional networks that confer appropriate connectivity onto cortical neurons. We describe evidence that Ldb genes are new players in the formation of long-distance connections, then describe a plan for performing a novel and innovative genome-widescreen to map out the transcriptional networks by which Ldb proteins and other transcription factors regulate specific patterns of cortical connectivity.
In light of evidence for aberrant cortical connectivity in autism and other neurodevelopmental disorders, our studies will provide novel and important insights into the fundamental genetic networks that control cortical development, and may reveal a hitherto hidden layer of regulatory domains that lie outside of gene coding regions, thus providing additional tools for analyzing genetic variations, associated with mental illness.
|Leone, Dino P; Panagiotakos, Georgia; Heavner, Whitney E et al. (2017) Compensatory Actions of Ldb Adaptor Proteins During Corticospinal Motor Neuron Differentiation. Cereb Cortex 27:1686-1699|
|Notwell, James H; Heavner, Whitney E; Darbandi, Siavash Fazel et al. (2016) TBR1 regulates autism risk genes in the developing neocortex. Genome Res 26:1013-22|
|Leone, Dino P; Heavner, Whitney E; Ferenczi, Emily A et al. (2015) Satb2 Regulates the Differentiation of Both Callosal and Subcerebral Projection Neurons in the Developing Cerebral Cortex. Cereb Cortex 25:3406-19|
|Wilson, Sandra L; Wilson, John P; Wang, Chengbing et al. (2012) Primary cilia and Gli3 activity regulate cerebral cortical size. Dev Neurobiol 72:1196-212|
|Shieh, Jennifer C; Schaar, Bruce T; Srinivasan, Karpagam et al. (2011) Endocytosis regulates cell soma translocation and the distribution of adhesion proteins in migrating neurons. PLoS One 6:e17802|
|Leone, Dino P; Srinivasan, Karpagam; Brakebusch, Cord et al. (2010) The rho GTPase Rac1 is required for proliferation and survival of progenitors in the developing forebrain. Dev Neurobiol 70:659-78|