R01NS124660

Roles of GSX Factors in Basal Ganglia Development

Normal brain function relies on the correct assembly of neural circuits during development. This process starts with the patterning of neural progenitors along the dorsal-ventral and anterior-posterior axes to give rise to distinct subtypes of neurons.

A number of key transcription factors (TFs) control the process of neuronal subtype specification. Work in the mouse has shown that the homeodomain (HD) TF GSX2 plays essential roles in the patterning and differentiation of neuronal cell types that arise from progenitors in the lateral ganglionic eminence (LGE) of the embryonic mouse telencephalon. These progenitors give rise to cell types that include the striatal projection neurons of the basal ganglia and interneurons in the olfactory bulb, both of which are severely reduced in mouse GSX2 mutants.

Accordingly, human patient studies identified 2 pathological GSX2 variant alleles in children with serious neurological symptoms, including dystonia and intellectual disabilities. Consistent with these symptoms, MRI imaging revealed severe basal ganglia agenesis. One GSX2 variant results in a null allele, however, the other is a missense variant (Q251R) that alters a key amino acid in the DNA binding HD.

We generated a mouse model of this human variant, and our initial studies suggest that the Q>R variant leads to a strong embryonic LGE and basal ganglia phenotype that is morphologically similar to embryos with GSX2 null alleles. Furthermore, our preliminary data indicate that this human HD variant alters GSX2 DNA binding specificity, and thereby may account for the observed phenotypes.

Moreover, we recently determined that GSX2 binds and regulates target genes via two mechanisms; as a monomer GSX2 represses gene expression whereas on a subset of DNA sites cooperative GSX2 binding to dimer sites appears to facilitate gene expression. Intriguingly, the DLX HD TFs, which lie downstream of GSX2 during LGE progenitor maturation, also bind monomer sites but instead of repressing they activate gene expression.

In this application, we propose to determine how GSX2 and the DLX TFs regulate LGE gene expression during basal ganglia development. To achieve this goal, we will test the following hypotheses in 3 independent specific aims:

1) To test the hypothesis that GSX2 controls basal ganglia development by mediating distinct gene regulatory outcomes in a DNA binding site-dependent manner.
2) To test the hypotheses that GSX2 and DLX TFs regulate a common set of LGE genes though direct competition for shared enhancer elements.
3) To test the hypothesis that the GSX2Q251R human variant causes altered DNA binding specificity, and thereby results in the mis-regulation of LGE gene expression and ultimately basal ganglia agenesis.

Our approach will combine the use of mouse genetics and human forebrain neural stem cell cultures with molecular, biochemical, and genomic approaches to study transcriptional control of neuronal specification in the developing basal ganglia. The unique expertise of our research team at CCHMC allows us to take this broad approach, and thus increases our chances to gain a deeper understanding of how GSX factors control basal ganglia development as well as to uncover new gene regulatory mechanisms that underlie dysfunction in certain childhood neurological disorders.

Childrens Hospital Medical Center

(1) TO SUPPORT EXTRAMURAL RESEARCH FUNDED BY THE NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE (NINDS) INCLUDING: BASIC RESEARCH THAT EXPLORES THE FUNDAMENTAL STRUCTURE AND FUNCTION OF THE BRAIN AND THE NERVOUS SYSTEM, RESEARCH TO UNDERSTAND THE CAUSES AND ORIGINS OF PATHOLOGICAL CONDITIONS OF THE NERVOUS SYSTEM WITH THE GOAL OF PREVENTING THESE DISORDERS, RESEARCH ON THE NATURAL COURSE OF NEUROLOGICAL DISORDERS, IMPROVED METHODS OF DISEASE PREVENTION, NEW METHODS OF DIAGNOSIS AND TREATMENT, DRUG DEVELOPMENT, DEVELOPMENT OF NEURAL DEVICES, CLINICAL TRIALS, AND RESEARCH TRAINING IN BASIC, TRANSLATIONAL AND CLINICAL NEUROSCIENCE. THE INSTITUTE IS THE LARGEST FUNDER OF BASIC NEUROSCIENCE IN THE US AND SUPPORTS RESEARCH ON TOPICS INCLUDING BUT NOT LIMITED TO: DEVELOPMENT OF THE NERVOUS SYSTEM, INCLUDING NEUROGENESIS AND PROGENITOR CELL BIOLOGY, SIGNAL TRANSDUCTION IN DEVELOPMENT AND PLASTICITY, AND PROGRAMMED CELL DEATH, SYNAPSE FORMATION, FUNCTION, AND PLASTICITY, LEARNING AND MEMORY, CHANNELS, TRANSPORTERS, AND PUMPS, CIRCUIT FORMATION AND MODULATION, BEHAVIORAL AND COGNITIVE NEUROSCIENCE, SENSORIMOTOR LEARNING, INTEGRATION AND EXECUTIVE FUNCTION, NEUROENDOCRINE SYSTEMS, SLEEP AND CIRCADIAN RHYTHMS, AND SENSORY AND MOTOR SYSTEMS. IN ADDITION, THE INSTITUTE SUPPORTS BASIC, TRANSLATIONAL AND CLINICAL STUDIES ON A NUMBER OF DISORDERS OF THE NERVOUS SYSTEM INCLUDING (BUT NOT LIMITED TO): STROKE, TRAUMATIC INJURY TO THE BRAIN, SPINAL CORD AND PERIPHERAL NERVOUS SYSTEM, NEURODEGENERATIVE DISORDERS, MOVEMENT DISORDERS, BRAIN TUMORS, CONVULSIVE DISORDERS, INFECTIOUS DISORDERS OF THE BRAIN AND NERVOUS SYSTEM, IMMUNE DISORDERS OF THE BRAIN AND NERVOUS SYSTEM, INCLUDING MULTIPLE SCLEROSIS, DISORDERS RELATED TO SLEEP, AND PAIN. PROGRAMMATIC AREAS, WHICH ARE PRIMARILY SUPPORTED BY THE DIVISION OF NEUROSCIENCE, ARE ALSO SUPPORTED BY THE DIVISION OF EXTRAMURAL ACTIVITIES, THE DIVISION OF TRANSLATIONAL RESEARCH, THE DIVISION OF CLINICAL RESEARCH, THE OFFICE OF TRAINING AND WORKFORCE DEVELOPMENT, THE OFFICE OF PROGRAMS TO ENHANCE NEUROSCIENCE WORKFORCE DEVELOPMENT, AND THE OFFICE OF INTERNATIONAL ACTIVITIES. (2) TO EXPAND AND IMPROVE THE SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. TO UTILIZE THE SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM, TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.853 - Extramural Research Programs in the Neurosciences and Neurological Disorders

National Institute of Neurological Disorders and Stroke (NNDS) [HHS - NIH]

Cincinnati, Ohio 45229 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 381% from $623,676 to $3,000,401.