Intranuclear rodlets (INRs) are poorly understood intranuclear bodies originally identified within neuronal nuclei on the basis of their unique morphology. Their mechanism of formation, biochemical composition and physiological significance are largely unknown. To gain insight into the molecular regulators of INR formation, mice with a conditional adult β cell-specific knockout of the master regulator of β-cell metabolism, Lkb1 protein kinase (LABKO mice) were studied. The proportion of beta cells containing INRs was significantly reduced in LABKO mice. Further examination ruled out mTOR and Mark2 as downstream effectors of Lkb1 knockout INR phenotype. Instead it identified the mTOR pathway as an independent regulator of INR formation. To investigate INR changes in a pathophysiological context, β cell INRs were examined in two models of human metabolic syndrome: (1) mice maintained on a high-fat diet and (2) leptin-deficient ob/ob mice. Significant INR reduction was observed in both models. Taken together, our results support the view that INR formation in pancreatic β cells is a dynamic and regulated process. The substantial depletion of INRs in LABKO and obese diabetic mice suggests their relationship to β cell function and potential involvement in diabetes pathogenesis. The significance of these findings was further underscored by the demonstration of INRs in human endocrine pancreas, suggesting their potential relevance to the development of metabolic syndrome in humans.
The existence of biochemically distinct subtypes of INRs has been suggested by previous reports of differential immunological staining of INRs in neurochemically distinct neuronal populations. Here, a novel variant of INR has been identified that is immunoreactive for the 40kDa huntingtin associated protein and ubiquitin; and evidence was provided for the existence of additional INR subtypes sharing ubiquitin immunoreactivity as a common feature. Selective association of these INRs with melanin concentrating hormone and tyrosine hydroxylase immunoreactive neurons of the hypothalamus and the locus coeruleus was described. It was also demonstrated for the first time that biochemically distinct INR subtypes can co-exist within a single nucleus where they engage in non-random spatial interactions. These findings highlight the biochemical diversity and cell type specific expression of these enigmatic intranuclear structures. On the basis of these findings and previous literature a hypothesis is proposed as to the overall functional significance of INRs in the cell nucleus.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:OOU-OLD./23848 |
| Date | 28 February 2013 |
| Creators | Milman, Pavel |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | Thèse / Thesis |
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