We are interested in the basic programs that govern the development of the mammalian forebrain and in how these basic programs vary during evolution, among individuals, and in neuropsychiatric disorders. We use human brains, human induced pluripotent stem cells (iPSC) which we differentiate into cerebral organoids, and rodent models. We have generated a biobank encompassing several hundreds of iPSC lines from families with autism, Tourette syndrome, and other developmental disorders. Our analytical tools include immunocytochemistry, imaging and molecular techniques to study how neural stem cells differentiate and connect to each other, and high throughput sequencing for the analysis of cellular genomes, transcriptomes and genomic regulatory regions. Our primary goal is the integration of cellular, molecular and genomic data to achieve a better understanding of how stem and progenitor cells differentiate and mature into different types of neurons that populate different regions of the human brain.
This collaborative interdepartmental program is leading interdisciplinary studies on iPSCs, somatic mosaicism, neural stem cells and human development. It includes investigators from the Yale Child Study Center, the Departments of Neuroscience, Pathology, Genetics, Molecular Biology and Biophysics, and laboratories at Stanford and the Mayo Clinic.
This collaborative multi-site project is generating a catalog of coding and noncoding RNAs and regulatory DNA elements in the developing and adult human brain and psychiatric disorders like schizophrenia, autism, and bipolar disorder.
This multi-site project is working to identify the extent and type of somatic mutations in brain cell lineages and psychiatric disorders such as autism, Tourette syndrome, bipolar disorder, and schizophrenia.
Somatic mosaicism is the accumulation of mutations in DNA sequence or copy number in cellular genomes after fertilization (typically in the form of copy number variations, single nucleotide mutations, new retrotransposon insertions).
In our lab we produce iPSC from skin fibroblasts of ASD patients and control subjects and use them to study differences in human embryonic neuronal development between these two populations.
Using stereology, we showed a decrease in number of GABAergic and cholinergic interneurons in postmortem basal ganglia tissue from subjects with Tourette.
Our studies have shown that Fgf signaling regulates the surface expansion of the cerebral cortex and the hippocampus.