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Principal Investigator: JAMES Y.H LI
Organization: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
Fiscal Year: 2024
Award: $530,585
Funding agency: National Institute of Neurological Disorders and Stroke
SUMMARY
Abnormalities in cerebellar development, especially pathology and dysfunction of Purkinje cells, have
been implicated in a wide variety of neurodevelopmental diseases, including ataxia, autism spectrum
disorder, schizophrenia, and language impairment. Being one of the earliest-born cerebellar cell groups,
Purkinje cells are believed instrumental in the development, function, and pathogenesis of the cerebellum.
Evidence suggests the existence of Purkinje cell subtypes with distinct molecular features. However, the
molecular mechanisms underlying the diversification of Purkinje cells remain poorly understood.
Consequently, we lack an entry to assess the role of individual Purkinje cell subtypes. Through single-cell
RNA and chromatin accessibility analyses, we uncovered at least nine molecularly distinct subtypes of
Purkinje cells in the developing mouse cerebellum. These Purkinje cell subtypes contribute to different
compartments in the developing cerebellum. Remarkably, the Purkinje cell subtypes display a
characteristic combinatorial expression of Foxp1, Foxp2, and Foxp4, which belong to a subgroup of the
forkhead-box transcription factor family. Mutations of human FOXP1 or FOXP2 are linked to speech
disorders, autism spectrum disorder, and intellectual disability, indicating that these proteins coordinate the
development of the neural circuits related to cognitive diseases. In vitro evidence shows that FoxP
proteins form dimers or oligomers with variable transcriptional targets and actives depending on the
binding partner. We hypothesize that Foxp1/2/4 form combinatorial “FoxP codes” to specify distinct
Purkinje cell subtypes, which in turn control the morphogenesis of the cerebellum. Aim 1 will combine
conventional expression analysis, spatial transcriptomics, and volume imaging to determine the
development of PC subtypes in relation to the morphogenesis of the cerebellum. Aim 2 will
delete Foxp1/2/4, individually and in combinations, from the mouse cerebellum. We will use histology,
single-cell RNA-seq, and behavioral studies to evaluate the impacts of single and
compound Foxp1/2/4 mutations on cerebellar development and behavioral function. Aim 3 will use a multi-
omic approach to study the molecular mechanism by which combinatorial FoxP genes regulate the
transcription program for Purkinje cell differentiation. At the completion of this project, we expect to have
identified the individual and combinatorial roles of Foxp1/2/4 in cerebellar development. This study will
have a significant positive impact, not only on the basic knowledge of cerebellar development but also on
the understanding of the molecular basis of the vast number of unexplored cerebellum-related diseases.
Terms: <ASD><ATAC sequencing><ATAC-seq><ATACseq><Abscission><Architecture><Assay><Assay for Transposase-Accessible Chromatin using sequencing><Ataxia><Ataxy><Autism><Autistic Disorder><Basal Transcription Factor><Basal transcription factor genes><Behavioral><Bilateral><Binding><Bioassay><Biological Assay><CAGH44><Cell Body><Cell Differentiation><Cell Differentiation process><Cells><Cerebellum><Characteristics><Chromatin><Code><Coding System><Cognition Disorders><Coordination Impairment><Cues><DNA Binding><DNA Binding Interaction><DNA bound><Data><Defect><Development><Disease><Disorder><Dysfunction><Dyssynergia><Early Infantile Autism><Embryo><Embryonic><Engineering / Architecture><Excision><Extirpation><FOXP1><FOXP1 gene><FOXP2><FOXP2 gene><Family><Forkhead Box P1><Forkhead Box P2><Functional disorder><Gene Transcription><General Transcription Factor Gene><General Transcription Factors><Genes><Genetic Alteration><Genetic Change><Genetic Transcription><Genetic defect><Genome><Glutamine-Rich Factor 1><Goals><Heterogeneity><Histology><Human><Image><In Vitro><Individual><Infantile Autism><Intellectual disability><Intellectual functioning disability><Intellectual limitation><Kanner's Syndrome><Knowledge><Link><Mental disorders><Mental health disorders><Mice><Mice Mammals><Modern Man><Molecular><Molecular Interaction><Morphogenesis><Movement><Murine><Mus><Mutation><Nerve Cells><Nerve Unit><Neural Cell><Neural Development><Neurocyte><Neurodevelopmental Disorder><Neurological Development Disorder><Neurons><Non-Polyadenylated RNA><Pathogenesis><Pathology><Phenotype><Physiopathology><Proteins><Psyche structure><Psychiatric Disease><Psychiatric Disorder><Purkinje Cells><Purkinje's Corpuscles><QRF1><RNA><RNA Expression><RNA Gene Products><Removal><Research><Ribonucleic Acid><Role><Schizophrenia><Schizophrenic Disorders><Specific qualifier value><Specified><Speech Disorders><Speech Manifestations><Subgroup><Surgical Removal><TNRC10><Testing><Transcription><Transcription Factor Proto-Oncogene><Transcription factor genes><Trinucleotide Repeat-Containing Gene 10><Ultrasonic><Ultrasonics><assay for transposase accessible chromatin followed by sequencing><assay for transposase accessible chromatin seq><assay for transposase accessible chromatin sequencing><assay for transposase-accessible chromatin with sequencing><autism spectral disorder><autism spectrum disorder><autistic spectrum disorder><behavior study><behavioral study><body movement><cellular differentiation><cerebellar Purkinje cell><cognitive disease><cognitive disorder><cognitive function><cognitive syndrome><combinatorial><dementia praecox><developmental><dimer><genome mutation><imaging><insight><intellectual and developmental disability><language impairment><limited intellectual functioning><mental><mental illness><morphogenetic process><multiomics><multiple omics><neural circuit><neural circuitry><neurocircuitry><neurodevelopment><neurodevelopmental disease><neuronal><panomics><pathophysiology><prevent><preventing><programs><prospective><psychiatric illness><psychological disorder><resection><scATAC sequencing><scATAC-seq><scRNA-seq><schizophrenic><single cell ATAC-seq><single cell ATAC-sequencing><single cell Assay for Transposase Accessible Chromatin sequencing><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell sequencing assay for transposase accessible chromatin><single cell transcriptomic profiling><single-cell Assay for Transposase-Accessible Chromatin with sequencing><single-cell RNA sequencing><single-cell assay for transposase-accessible chromatin using sequencing><single-cell assay for transposase-accessible chromatin-seq><social role><synaptic circuit><synaptic circuitry><transcription factor><transcriptomics><vocalization>