Dataset Information

Notch Dosage: Jagged1 Haploinsufficiency Is Associated With Reduced Neuronal Division and Disruption of Periglomerular Interneurons in Mice.

ABSTRACT: Neural stem cells in the lateral ganglionic eminence (LGE) generate progenitors that migrate through the rostral migratory stream (RMS) to repopulate olfactory bulb (OB) interneurons, but the regulation of this process is poorly defined. The evolutionarily conserved Notch pathway is essential for neural development and maintenance of neural stem cells. Jagged1, a Notch ligand, is required for stem cell maintenance. In humans, heterozygous mutations in JAGGED1 cause Alagille syndrome, a genetic disorder characterized by complications such as cognitive impairment and reduced number of bile ducts in the liver, suggesting the presence of a JAGGED1 haploinsufficient phenotype. Here, we examine the role of Jagged1 using a conditional loss-of-function allele in the nervous system. We show that heterozygous Jagged1 mice possess a haploinsufficient phenotype that is associated with a reduction in size of the LGE, a reduced proliferative state, and fewer progenitor cells in the LGE and RMS. Moreover, loss of Jagged1 leads to deficits in periglomerular interneurons in the OB. Our results support a dose-dependent role for Jagged1 in maintaining progenitor division within the LGE and RMS.

SUBMITTER: Blackwood CA

PROVIDER: S-EPMC7054221 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Notch Dosage<i>: Jagged1</i> Haploinsufficiency Is Associated With Reduced Neuronal Division and Disruption of Periglomerular Interneurons in Mice.

Blackwood Christopher A CA Bailetti Alessandro A Nandi Sayan S Gridley Thomas T Hébert Jean M JM

Frontiers in cell and developmental biology 20200226

Neural stem cells in the lateral ganglionic eminence (LGE) generate progenitors that migrate through the rostral migratory stream (RMS) to repopulate olfactory bulb (OB) interneurons, but the regulation of this process is poorly defined. The evolutionarily conserved Notch pathway is essential for neural development and maintenance of neural stem cells. Jagged1, a Notch ligand, is required for stem cell maintenance. In humans, heterozygous mutations in JAGGED1 cause Alagille syndrome, a genetic d ...[more]

PMID: 32161758

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Project description:Impaired mitochondrial function and aberrant neuronal network activity are believed to be early events in the pathogenesis of Alzheimer's disease (AD), but how mitochondrial alterations contribute to aberrant activity in neuronal circuits is unknown. In this study, we examined the function of mitochondrial protein deacetylase sirtuin 3 (SIRT3) in the pathogenesis of AD. Compared with AppPs1 mice, Sirt3-haploinsufficient AppPs1 mice (Sirt3+/-AppPs1) exhibit early epileptiform EEG activity and seizure. Both male and female Sirt3+/-AppPs1 mice were observed to die prematurely before 5 months of age. When comparing male mice among different genotypes, Sirt3 haploinsufficiency renders GABAergic interneurons in the cerebral cortex vulnerable to degeneration and associated neuronal network hyperexcitability. Feeding Sirt3+/-AppPs1 AD mice with a ketone ester-rich diet increases SIRT3 expression and prevents seizure-related death and the degeneration of GABAergic neurons, indicating that the aggravated GABAergic neuron loss and neuronal network hyperexcitability in Sirt3+/-AppPs1 mice are caused by SIRT3 reduction and can be rescued by increase of SIRT3 expression. Consistent with a protective role in AD, SIRT3 levels are reduced in association with cerebral cortical A? pathology in AD patients. In summary, SIRT3 preserves GABAergic interneurons and protects cerebral circuits against hyperexcitability, and this neuroprotective mechanism can be bolstered by dietary ketone esters.SIGNIFICANCE STATEMENT GABAergic neurons provide the main inhibitory control of neuronal activity in the brain. By preserving mitochondrial function, SIRT3 protects parvalbumin and calretinin interneurons against A?-associated dysfunction and degeneration in AppPs1 Alzheimer's disease mice, thus restraining neuronal network hyperactivity. The neuronal network dysfunction that occurs in Alzheimer's disease can be partially reversed by physiological, dietary, and pharmacological interventions to increase SIRT3 expression and enhance the functionality of GABAergic interneurons.

Project description:BACKGROUND:The inactivation of tumor suppressor genes follows Alfred Knudson's 'two-hit' model: both alleles need to be inactivated by independent mutation events to trigger tumor formation. However, in a minority of tumor suppressor genes a single hit is sufficient to initiate tumorigenesis notwithstanding the presence of the wild-type allele, a condition known as haploinsufficiency. The SMAD4 gene is an intracellular mediator of the TGF-beta and BMP signal transduction pathways and a tumor suppressor involved in pancreatic and colorectal tumorigenesis. In Smad4-mutant mouse models, haploinsufficiency characterizes the development of gastrointestinal polyps with initial retention of the wild-type allele and protein expression within the nascent tumors and in their direct microenvironment. Similarly, germline SMAD4 mutations are responsible for a subset of patients affected by juvenile polyposis syndrome, an autosomal dominant intestinal cancer syndrome. To date, the molecular and cellular consequences of SMAD4 haploinsufficiency on TGF-beta and BMP signaling and on genome-wide gene expression have not been investigated. RESULTS:Here we show that, similar to previous observations in Smad4-mutant mouse models, haploinsufficiency characterizes a substantial fraction of the juvenile polyps arising in patients with germline SMAD4 mutations. Also, mouse embryonic and intestinal cells heterozygous for a targeted Smad4 null mutation are characterized by a corresponding 50% reduction of the Smad4 protein levels. Reporter assays revealed that mouse Smad4+/- cells exert intermediate inhibitory effects on both TGF-beta and BMP signaling. Genome-wide expression profiling analysis of Smad4+/- and Smad4-/- cells pinpointed a subset of dosage-dependent transcriptional target genes encompassing, among others, members of the TGF-beta and Wnt signaling pathways. These SMAD4 dosage-dependent transcriptional changes were confirmed and validated in a subset of target genes in intestinal tissues from juvenile polyposis syndrome patients. CONCLUSION:Smad4 haploinsufficiency is sufficient to significantly inhibit both TGF-beta and BMP signal transduction and results in the differential expression of a broad subset of target genes likely to underlie tumor formation both from the mesenchymal and epithelial compartments. The results of our study, performed in normal rather than tumor cells where additional (epi-) genetic alterations may confound the analysis, are relevant for our understanding and elucidation of the initial steps underlying SMAD4-driven intestinal tumorigenesis.

Dataset Information

Notch Dosage: Jagged1 Haploinsufficiency Is Associated With Reduced Neuronal Division and Disruption of Periglomerular Interneurons in Mice.

Publications

Notch Dosage<i>: Jagged1</i> Haploinsufficiency Is Associated With Reduced Neuronal Division and Disruption of Periglomerular Interneurons in Mice.

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