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CRISPR/Cas9-induced zebrafish mutants for ebf3a and dhx30

ABSTRACT: Mutations in the transcription factor EBF3 results in a neurodevelopmental disorder, and studies in animal models indicate that it has a critical role in neuronal differentiation. The molecular pathways and neuron types disrupted by its loss, however, have not been thoroughly investigated. Nor have the outcomes of these changes on behavior and brain activity. Here, we generated and characterized a zebrafish ebf3a loss-of-function mutant. We discovered morphological and neural phenotypes, including an overall smaller brain size, particularly in the hypothalamus, cerebellum, and hindbrain. Brain function was also compromised, with activity strongly increased in the cerebellum and abnormal behavior at baseline and in response to visual and acoustic stimuli. From RNA-sequencing of developing larvae, notable changes included significant downregulation of genes that mark olfactory sensory neurons, the lateral line, and cerebellar Purkinje neurons. This study sets the stage for determining which downstream pathways underlie the emergence of the observed phenotypes and establishes multiple strong phenotypes that could form the basis of a drug screen.

ORGANISM(S): Danio rerio

PROVIDER: GSE276705 | GEO | 2024/09/09

REPOSITORIES: GEO

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Project description:Cellular diversification is a fundamental feature of the brain that is critical for physiological functions of the nervous system including perception, motor control, and learning and memory. Advances in single cell RNA-sequencing have led to characterization of transcriptomic profiles of distinct major types of neurons in the brain. However, how transcriptomic profiles diversify within a specific population of neurons and their links to function remain poorly understood. Purkinje neurons represent some of the most iconic cells in the brain with decades of research characterizing their anatomy, cell biology, physiology, and roles in plasticity, learning and memory, as well as in diseases of the nervous system. In this study, we deployed an approach of isolating nuclei tagged in specific cell types followed by cell sorting and single nuclear RNA sequencing to profile Purkinje neurons and their response to motor activity and learning in adult mice. We uncovered the molecular map of two major subpopulations of Purkinje neurons, identified by the hallmark genes Aldoc and Plcb4, which bear distinct transcriptomic features. Remarkably, Plcb4+, but not Aldoc+, Purkinje neurons display robust plasticity of gene expression in mice subjected to sensorimotor and learning experience with downregulation of gene clusters related to chromatin regulation and synaptic organization and upregulation of gene clusters related to neuronal activity and synaptic transmission and neuron-immune interactions. Using in vivo calcium imaging and optogenetics perturbation approaches, we show that activation of Plcb4+ Purkinje neuron plays a crucial role in associative motor learning. Upon integrating single nuclear RNA-seq datasets with weighted gene network analysis, we also identify a motor activity and learning specific gene module that includes components of the FGFR2-SOS1-MAPK signaling pathway in Plcb4+ Purkinje neurons. Knockout of FGFR2 in Plcb4+ Purkinje neurons in adult mice by a CRISPR approach dramatically disrupts motor learning. Our findings provide a platform for identification of subpopulations of neurons and define how diversification of Purkinje neurons in the cerebellum links to their responses to motor learning. Our study, and by extension similar studies in the human brain, will provide the foundation for understanding the selective vulnerability of Plcb4+ Purkinje neurons to neurological diseases.

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CRISPR/Cas9-induced zebrafish mutants for ebf3a and dhx30

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