Loss of BAF complex in developing cortex perturbs radial neuronal migration in a WNT signaling-dependent manner
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA732078 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR14624525.fastq.gz | Fastqsanger.gz | |||
| SRR14624526.fastq.gz | Fastqsanger.gz | |||
| SRR14624527.fastq.gz | Fastqsanger.gz | |||
| SRR14624528.fastq.gz | Fastqsanger.gz | |||
| SRR14624529.fastq.gz | Fastqsanger.gz |
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Project description:Radial neuronal migration is a key neurodevelopmental event indispensable for proper cortical laminar organization. Cortical neurons mainly use glial fiber guides, cell adhesion dynamics, and cytoskeletal remodeling, among other discrete processes, to radially trek from their birthplace to final layer positions. Dysregulated radial migration can engender cortical mis-lamination, leading to neurodevelopmental disorders. Epigenetic factors, including chromatin remodelers have emerged as formidable regulators of corticogenesis. Notably, the chromatin remodeler BAF complex has been shown to regulate several aspects of cortical histogenesis. Nonetheless, our understanding of how BAF complex regulates neuronal migration is limited. Here, we report that BAF complex is required for neuron migration during cortical development. Ablation of BAF complex in the developing mouse cortex caused alteration in the cortical gene expression program, leading to loss of radial migration-related factors critical for proper cortical layer formation. Of note, BAF complex inactivation in cortex caused defective neuronal polarization resulting in diminished multipolar-to-bipolar transition and eventual disruption of radial migration of cortical neurons. The abnormal radial migration and cortical mis-lamination can be partly rescued by downregulating WNT signaling hyperactivity in the BAF complex mutant cortex. By implication, the BAF complex modulates WNT signaling to establish the gene expression program required for glial fiber-dependent neuronal migration, and cortical lamination. Overall, BAF complex has been identified to be crucial for cortical morphogenesis through instructing multiple aspects of radial neuronal migration in a WNT signaling-dependent manner.
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Project description:The mammalian neocortex is composed of diverse neuronal and glial cell classes that broadly arrange in six distinct laminae. Cortical layers emerge during development and defects in the developmental programs that orchestrate cortical lamination are associated with neurodevelopmental diseases. The developmental principle of cortical layer formation is based on concerted radial projection neuron migration, from their birthplace to their final target position. Radial migration occurs in defined sequential steps that are regulated by a large array of signaling pathways. However, based on genetic loss-offunction experiments, most studies have thus far focused on the role of cell-autonomous gene function. Yet, cortical neuron migration in situ is a complex process and migrating neurons traverse along diverse cellular compartments and environments. The role of tissue-wide properties and genetic state in radial neuron migration is however not well understood. Here, we utilized Mosaic Analysis with Double Markers (MADM) technology to either sparsely or globally delete gene function followed by quantitative single cell phenotyping. The MADM-based gene ablation paradigms in combination with computational modeling demonstrated that global tissue-wide effects predominates cell-autonomous gene function albeit in a gene-specific manner. Our results thus suggest that the genetic landscape in a tissue critically impacts the overall migration phenotype of individual cortical projection neurons. In a broader context our findings imply that global tissue-wide effects represent an essential component of the underlying etiology associated with focal malformations of cortical development (FMCD) in particular, and neurological diseases in general.
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Project description:During adult neurogenesis, newly formed olfactory bulb (OB) interneurons migrate radially to integrate into specific layers of the OB. Despite the importance of this process, the intracellular mechanisms that regulate radial migration remain poorly understood. Here we find that microRNA (miRNA) let-7 regulates radial migration by modulating autophagy in new-born neurons. Using Argonaute2-immunoprecipitation, we performed global profiling of miRNAs in adult-born OB neurons and identified let-7 as a highly abundant miRNA family. Knockdown of let-7 in migrating neuroblasts prevented radial migration and led to an immature morphology of newly formed interneurons. This phenotype was accompanied by a decrease in autophagic activity. Overexpression of Beclin-1 or TFEB in new-born neurons lacking let-7 resulted in re-activation of autophagy and restored radial migration. Thus, these results reveal a miRNA-dependent link between autophagy and adult neurogenesis with implications for neurodegenerative diseases where these processes are impaired.
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