Tumor suppressor menin is required for subunit-specific nAChR α5 transcription and nAChR-dependent presynaptic facilitation in cultured mouse hippocampal neurons

Getz, Angela M.; Xu, Fenglian; Visser, Frank; Persson, Roger; Syed, Naweed I.

doi:10.1038/s41598-017-01825-x

Cited by 12 publications

(27 citation statements)

References 72 publications

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“…Hippocampal neurons were dissected from B6 mice and cultured from newborn pups (postnatal day 2, P2) as described previously 83 , 84 . Briefly, hippocampal tissue was isolated and single cells were dissociated with papain (50 µg/mL).…”

Section: Methodsmentioning

confidence: 99%

Adropin correlates with aging-related neuropathology in humans and improves cognitive function in aging mice

et al. 2021

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The neural functions of adropin, a secreted peptide highly expressed in the brain, have not been investigated. In humans, adropin is highly expressed in astrocytes and peaks during critical postnatal periods of brain development. Gene enrichment analysis of transcripts correlating with adropin expression suggests processes relevant to aging-related neurodegenerative diseases that vary with age and dementia state, possibly indicating survivor bias. In people aged <40 y and ‘old-old’ (>75 y) diagnosed with dementia, adropin correlates positively with genes involved in mitochondrial processes. In the ‘old-old’ without dementia adropin expression correlates positively with morphogenesis and synapse function. Potent neurotrophic responses in primary cultured neurons are consistent with adropin supporting the development and function of neural networks. Adropin expression in the ‘old-old’ also correlates positively with protein markers of tau-related neuropathologies and inflammation, particularly in those without dementia. How variation in brain adropin expression affects neurological aging was investigated using old (18-month) C57BL/6J mice. In mice adropin is expressed in neurons, oligodendrocyte progenitor cells, oligodendrocytes, and microglia and shows correlative relationships with groups of genes involved in neurodegeneration and cellular metabolism. Increasing adropin expression using transgenesis improved spatial learning and memory, novel object recognition, resilience to exposure to new environments, and reduced mRNA markers of inflammation in old mice. Treatment with synthetic adropin peptide also reversed age-related declines in cognitive functions and affected expression of genes involved in morphogenesis and cellular metabolism. Collectively, these results establish a link between adropin expression and neural energy metabolism and indicate a potential therapy against neurological aging.

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Section: Methodsmentioning

confidence: 99%

Adropin correlates with aging-related neuropathology in humans and improves cognitive function in aging mice

et al. 2021

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“…The gene is located on chromosome 11q13 and encodes a multifunctional nuclear scaffold protein menin with a known role in the regulation of transcription, proliferation, differentiation, and genomic integrity. 17 It is highly conserved among species ( Figure 2B) and shows a ubiquitous expression beyond tissues typically affected by MEN1 syndrome, including cortex, hippocampus, brainstem, and cerebellum. 18,19 Immunohistochemistry and antibody staining in the murine brain show the strongest labeling in the pyramidal cells of the hippocampus (http:// mouse.brain-map.org).…”

Section: Discussionmentioning

confidence: 99%

A somatic mutation in MEN1 gene detected in periventricular nodular heterotopia tissue obtained from depth electrodes

et al. 2019

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Periventricular nodular heterotopia (PNH) is a common structural malformation of cortical development. Mutations in the filamin A gene are frequent in familial cases with X‐linked PNH. However, many cases with sporadic PNH remain genetically unexplained. Although medically refractory epilepsy often brings attention to the underlying PNH, patients are often not candidates for surgical resection. This limits access to neuronal tissue harboring causal mutations. We evaluated a patient with PNH and medically refractory focal epilepsy who underwent a presurgical evaluation with stereotactically placed electroencephalographic (SEEG) depth electrodes. Following SEEG explantation, we collected trace tissue adherent to the electrodes and extracted the DNA. Whole‐exome sequencing performed in a Clinical Laboratory Improvement Amendments–approved genetic diagnostic laboratory uncovered a de novo heterozygous pathogenic variant in novel candidate PNH gene MEN1 (multiple endocrine neoplasia type 1; c.1546dupC, p.R516PfsX15). The variant was absent in an earlier exome profiling of the venous blood–derived DNA. The MEN1 gene encodes the ubiquitously expressed, nuclear scaffold protein menin, a known tumor suppressor gene with an established role in the regulation of transcription, proliferation, differentiation, and genomic integrity. Our study contributes a novel candidate gene in PNH generation and a novel practical approach that integrates electrophysiological and genetic explorations of epilepsy.

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“…Neuronal Cell Culture, Phase Contrast Imaging Hippocampal neurons were dissected from B6 mice and cultured from newborn pups (postnatal day 2, P2) as described previously 87,88 . Brie y, hippocampal tissue was isolated and single cells were dissociated with papain (50 µg/mL).…”

Section: Measurements Of Gene and Protein Expressionmentioning

confidence: 99%

Adropin expression correlates with age-related neuropathologies in the human brain and improves neuroinflammation and cognitive function in aging mice

Banerjee

Ghoshal

Girardet

et al. 2021

Preprint

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Adropin is most abundant in neural tissues yet its neurological functions are unclear. Data from post-mortem human brain tissue samples indicates adropin expression occurs predominantly in astrocytes, peaks during critical post-natal periods of brain development, and then declines with aging. Previous experiments indicate adropin regulates mitochondrial metabolism. Gene clusters correlating with adropin are age- and dementia-specific, possibly indicating survivor bias. In people aged <40y adropin correlates positively with genes involved in mitochondrial metabolism, APOE and Clusterin. In the ‘old-old’ (>75y) with dementia, adropin expression correlates with genes linked to mitochondrial metabolism and neurodegenerative conditions. In the ‘old-old’ (>75y) without dementia, adropin correlates with genes involved in morphogenesis, growth of neuronal processes (dendrites, axons) and synapse function. Accordingly, adropin elicits neurotrophic responses in primary cultured neurons. Adropin expression also correlates positively with protein markers of tau-related neuropathologies and inflammation, particularly in people without dementia, indicating a link to cellular stressors. How variation in brain adropin expression affects neurological aging was investigated using C57BL/6J mice. In mice, adropin is more widely expressed in neurons, oligodendrocyte progenitor cells, oligodendrocytes, and microglia. Preventing the decline in expression observed with aging of mice using transgenesis improved cognitive function and resilience, while also reducing mRNA markers of inflammation in 18-month old mice. Treating 18-month old mice with adropin peptide also improved cognitive performance. These results link adropin expression to cellular energy metabolism and stress responses in the brain and indicates a possible relationship with aging-related cognitive decline.

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Tumor suppressor menin is required for subunit-specific nAChR α5 transcription and nAChR-dependent presynaptic facilitation in cultured mouse hippocampal neurons

Cited by 12 publications

References 72 publications

Adropin correlates with aging-related neuropathology in humans and improves cognitive function in aging mice

Adropin correlates with aging-related neuropathology in humans and improves cognitive function in aging mice

A somatic mutation in MEN1 gene detected in periventricular nodular heterotopia tissue obtained from depth electrodes

Adropin expression correlates with age-related neuropathologies in the human brain and improves neuroinflammation and cognitive function in aging mice

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