There are two main goals of this project. In the first, we hope to gain a better understanding of a novel mechansim of RNA depednent transcriptional regulation. In the second, we hope to gain a better understanding of how GABAergic neuronal differentiation and migration are comtrolled. The first goal focuses on how the novel non-coding RNAs, embryonic ventral forebrain (Evf), influence transcription of the Dlx 5/6 enhancer. Evf ncRNAs are the first developmentally regulated ncRNAs to be discovered that affect the transcriptional activity of a homeodomain protein. Evf ncRNAs are also the first ncRNAs shown to cooperate and complex with a homeobox-containing transcription factor. The proposed studies would therefore be the first to investigate the in vivo role of developmentally regulated ncRNA-dependent modulation of enhancer activity. The importance of mechanistic studies of RNA function is clear from the number of regulatory RNAs thought to be involved different diseases. These include: Prader Willi Syndrome, diGeorge Syndrome, Beckwith-Wiedeman syndrome, Spinocerebellar ataxia type 8, and campomelic dysplasia.
We hypothesize that Evfs are effectors of the Dlx 1/2 genes, modulating the levels of Dlx 5 and 6 within neurons. Dlx genes are known to be required for proper GABAergic migration and/or survival to the cortex and hippocampus. Most recently, it was demonstrated that the loss of specific Dlx-1 GABAergic subpopulations results in a mouse model of epilepsy. In addition, alterations in Dlx 5 imprinting has been linked to Rett syndrome, affecting specific aspects of GABAergioc interneuron differentiation or migration. Since altered GABAergic interneuron function has been linked to epilepsy, autism, schizophrenia, and mental retardation, studies on the normal development of GABAergic interneurons are critical to understanding the molecular bases for these diseases. Ultimately, we hope that a better understanding of the normal development of specific neuronal subpopulations in the brain will lead to the prevention and treatment of human neurological diseases.
| Qi, Jin; Kim, Minjung; Sanchez, Russell et al. (2018) Enhanced susceptibility to stress and seizures in GAD65 deficient mice. PLoS One 13:e0191794 |
| Cajigas, Ivelisse; Leib, David E; Cochrane, Jesse et al. (2015) Evf2 lncRNA/BRG1/DLX1 interactions reveal RNA-dependent inhibition of chromatin remodeling. Development 142:2641-52 |
| Berghoff, Emily G; Clark, Mary F; Chen, Sean et al. (2013) Evf2 (Dlx6as) lncRNA regulates ultraconserved enhancer methylation and the differential transcriptional control of adjacent genes. Development 140:4407-16 |
| Kohtz, Jhumku D; Berghoff, Emily G (2010) Regulatory long non-coding RNAs and neuronal disorders. Physiol Behav 100:250-4 |
| Himmelstein, Diana S; Bi, Chunming; Clark, Brian S et al. (2010) Balanced Shh signaling is required for proper formation and maintenance of dorsal telencephalic midline structures. BMC Dev Biol 10:118 |
