Deletion of Wnt10a Is Implicated in Hippocampal Neurodegeneration in Mice

Zhang, Jia-He; Tasaki, Takashi; Tsukamoto, Manabu; Wang, Ke-Yong; Kubo, Kin‐ya; Chen, Huayue

doi:10.3390/biomedicines10071500

Cited by 8 publications

(5 citation statements)

References 56 publications

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“…10c ). WNT signalling is known to be important for hippocampal functions 50 , as well as dysfunction in neurological disorders, such as spatial memory impairment and anxiety-like behaviour 51 . Chandelier neurons and CA3 glutamatergic neurons have also been implicated in these neurological disorders 52 , 53 .…”

Section: Cell-type-specific Cell–cell Interactions and Communicationsmentioning

confidence: 99%

Molecularly defined and spatially resolved cell atlas of the whole mouse brain

Zhang,

Pan,

Jung

et al. 2023

Nature

141

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In mammalian brains, millions to billions of cells form complex interaction networks to enable a wide range of functions. The enormous diversity and intricate organization of cells have impeded our understanding of the molecular and cellular basis of brain function. Recent advances in spatially resolved single-cell transcriptomics have enabled systematic mapping of the spatial organization of molecularly defined cell types in complex tissues1–3, including several brain regions (for example, refs. 1–11). However, a comprehensive cell atlas of the whole brain is still missing. Here we imaged a panel of more than 1,100 genes in approximately 10 million cells across the entire adult mouse brains using multiplexed error-robust fluorescence in situ hybridization12 and performed spatially resolved, single-cell expression profiling at the whole-transcriptome scale by integrating multiplexed error-robust fluorescence in situ hybridization and single-cell RNA sequencing data. Using this approach, we generated a comprehensive cell atlas of more than 5,000 transcriptionally distinct cell clusters, belonging to more than 300 major cell types, in the whole mouse brain with high molecular and spatial resolution. Registration of this atlas to the mouse brain common coordinate framework allowed systematic quantifications of the cell-type composition and organization in individual brain regions. We further identified spatial modules characterized by distinct cell-type compositions and spatial gradients featuring gradual changes of cells. Finally, this high-resolution spatial map of cells, each with a transcriptome-wide expression profile, allowed us to infer cell-type-specific interactions between hundreds of cell-type pairs and predict molecular (ligand–receptor) basis and functional implications of these cell–cell interactions. These results provide rich insights into the molecular and cellular architecture of the brain and a foundation for functional investigations of neural circuits and their dysfunction in health and disease.

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Section: Cell-type-specific Cell–cell Interactions and Communicationsmentioning

confidence: 99%

Molecularly defined and spatially resolved cell atlas of the whole mouse brain

Zhang,

Pan,

Jung

et al. 2023

Nature

141

View full text Add to dashboard Cite

show abstract

“…Interestingly, the proximal pairs of chandelier neurons and CA3 Glut neurons showed pronounced upregulation of ligand-receptor pairs in the Wnt pathways ( Figure 6i ). Wnt signaling is known to be important for hippocampal functions 81 , as well as dysfunction in neurological disorders, such as spatial memory impairment and anxiety-like behavior 82 . Chandelier neurons and CA3 Glut neurons have been previously implicated in these neurological disorders 83, 84 , but whether our observed interactions between chandelier and CA3 Glut neurons are involved in these disorders awaits future investigations.…”

Section: Introductionmentioning

confidence: 99%

A molecularly defined and spatially resolved cell atlas of the whole mouse brain

Zhang

Pan

Halpern

et al. 2023

Preprint

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In mammalian brains, tens of millions to billions of cells form complex interaction networks to enable a wide range of functions. The enormous diversity and intricate organization of cells in the brain have so far hindered our understanding of the molecular and cellular basis of its functions. Recent advances in spatially resolved single-cell transcriptomics have allowed systematic mapping of the spatial organization of molecularly defined cell types in complex tissues. However, these approaches have only been applied to a few brain regions and a comprehensive cell atlas of the whole brain is still missing. Here, we imaged a panel of >1,100 genes in ~8 million cells across the entire adult mouse brain using multiplexed error-robust fluorescence in situ hybridization (MERFISH) and performed spatially resolved, single-cell expression profiling at the whole-transcriptome scale by integrating MERFISH and single-cell RNA-sequencing (scRNA-seq) data. Using this approach, we generated a comprehensive cell atlas of >5,000 transcriptionally distinct cell clusters, belonging to ~300 major cell types, in the whole mouse brain with high molecular and spatial resolution. Registration of the MERFISH images to the common coordinate framework (CCF) of the mouse brain further allowed systematic quantifications of the cell composition and organization in individual brain regions defined in the CCF. We further identified spatial modules characterized by distinct cell-type compositions and spatial gradients featuring gradual changes in the gene-expression profiles of cells. Finally, this high-resolution spatial map of cells, with a transcriptome-wide expression profile associated with each cell, allowed us to infer cell-type-specific interactions between several hundred pairs of molecularly defined cell types and predict potential molecular (ligand-receptor) basis and functional implications of these cell-cell interactions. These results provide rich insights into the molecular and cellular architecture of the brain and a valuable resource for future functional investigations of neural circuits and their dysfunction in diseases.

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“…WNT10A reported an SNV in exon 3. WNT10A −/− knockout mice exhibited spatial memory impairment and anxiety-like behaviour (Zhang et al 2022 ). WNT10A deficiency was proven to cause hippocampal neuro-degeneration in mice indicating similar effects in AD patients .…”

Section: Resultsmentioning

confidence: 99%

Exome sequence analysis of rare frequency variants in Late-Onset Alzheimer Disease

Sundarrajan¹,

Venkatesan²,

et al. 2023

Metab Brain Dis

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Alzheimer disease (AD) is a leading cause of dementia in elderly patients who continue to live between 3 and 11 years of diagnosis. A steep rise in AD incidents is observed in the elderly population in East-Asian countries. The disease progresses through several changes, including memory loss, behavioural issues, and cognitive impairment. The etiology of AD is hard to determine because of its complex nature. The whole exome sequences of late-onset AD (LOAD) patients of Korean origin are investigated to identify rare genetic variants that may influence the complex disorder. Computational annotation was performed to assess the function of candidate variants in LOAD. The in silico pathogenicity prediction tools such as SIFT, Polyphen-2, Mutation Taster, CADD, LRT, PROVEAN, DANN, VEST3, fathmm-MKL, GERP + + , SiPhy, phastCons, and phyloP identified around 17 genes harbouring deleterious variants. The variants in the ALDH3A2 and RAD54B genes were pathogenic, while in 15 other genes were predicted to be variants of unknown significance. These variants can be potential risk candidates contributing to AD. In silico computational techniques such as molecular docking, molecular dynamic simulation and steered molecular dynamics were carried out to understand the structural insights of RAD54B with ATP. The simulation of mutant (T459N) RAD54B with ATP revealed reduced binding strength of ATP at its binding site. In addition, lower binding free energy was observed when compared to the wild-type RAD54B. Our study shows that the identified uncommon variants are linked to AD and could be probable predisposing genetic factors of LOAD.

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Deletion of Wnt10a Is Implicated in Hippocampal Neurodegeneration in Mice

Cited by 8 publications

References 56 publications

Molecularly defined and spatially resolved cell atlas of the whole mouse brain

Molecularly defined and spatially resolved cell atlas of the whole mouse brain

A molecularly defined and spatially resolved cell atlas of the whole mouse brain

Exome sequence analysis of rare frequency variants in Late-Onset Alzheimer Disease

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