Dataset Information

An absence of nuclear lamins in keratinocytes leads to ichthyosis, defective epidermal barrier function, and intrusion of nuclear membranes and endoplasmic reticulum into the nuclear chromatin.

ABSTRACT: B-type lamins (lamins B1 and B2) have been considered to be essential for many crucial functions in the cell nucleus (e.g., DNA replication and mitotic spindle formation). However, this view has been challenged by the observation that an absence of both B-type lamins in keratinocytes had no effect on cell proliferation or the development of skin and hair. The latter findings raised the possibility that the functions of B-type lamins are subserved by lamins A and C. To explore that idea, we created mice lacking all nuclear lamins in keratinocytes. Those mice developed ichthyosis and a skin barrier defect, which led to death from dehydration within a few days after birth. Microscopy of nuclear-lamin-deficient skin revealed hyperkeratosis and a disordered stratum corneum with an accumulation of neutral lipid droplets; however, BrdU incorporation into keratinocytes was normal. Skin grafting experiments confirmed the stratum corneum abnormalities and normal BrdU uptake. Interestingly, the absence of nuclear lamins in keratinocytes resulted in an interspersion of nuclear/endoplasmic reticulum membranes with the chromatin. Thus, a key function of the nuclear lamina is to serve as a "fence" and prevent the incursion of cytoplasmic organelles into the nuclear chromatin.

SUBMITTER: Jung HJ

PROVIDER: S-EPMC4248738 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature

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An absence of nuclear lamins in keratinocytes leads to ichthyosis, defective epidermal barrier function, and intrusion of nuclear membranes and endoplasmic reticulum into the nuclear chromatin.

Jung Hea-Jin HJ Tatar Angelica A Tu Yiping Y Nobumori Chika C Yang Shao H SH Goulbourne Chris N CN Herrmann Harald H Fong Loren G LG Young Stephen G SG

Molecular and cellular biology 20141013 24

B-type lamins (lamins B1 and B2) have been considered to be essential for many crucial functions in the cell nucleus (e.g., DNA replication and mitotic spindle formation). However, this view has been challenged by the observation that an absence of both B-type lamins in keratinocytes had no effect on cell proliferation or the development of skin and hair. The latter findings raised the possibility that the functions of B-type lamins are subserved by lamins A and C. To explore that idea, we creat ...[more]

PMID: 25312645

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Project description:SEPN1-related myopathy (SEPN1-RM) is a muscle disorder due to mutations of the SEPN1 gene, which is characterized by muscle weakness and fatigue leading to scoliosis and life-threatening respiratory failure. Core lesions, focal areas of mitochondria depletion in skeletal muscle fibers, are the most common histopathological lesion. SEPN1-RM underlying mechanisms and the precise role of SEPN1 in muscle remained incompletely understood, hindering the development of biomarkers and therapies for this untreatable disease. To investigate the pathophysiological pathways in SEPN1-RM, we performed metabolic studies, calcium and ATP measurements, super-resolution and electron microscopy on in vivo and in vitro models of SEPN1 deficiency as well as muscle biopsies from SEPN1-RM patients. Mouse models of SEPN1 deficiency showed marked alterations in mitochondrial physiology and energy metabolism, suggesting that SEPN1 controls mitochondrial bioenergetics. Moreover, we found that SEPN1 was enriched at the mitochondria-associated membranes (MAM), and was needed for calcium transients between ER and mitochondria, as well as for the integrity of ER-mitochondria contacts. Consistently, loss of SEPN1 in patients was associated with alterations in body composition which correlated with the severity of muscle weakness, and with impaired ER-mitochondria contacts and low ATP levels. Our results indicate a role of SEPN1 as a novel MAM protein involved in mitochondrial bioenergetics. They also identify a systemic bioenergetic component in SEPN1-RM and establish mitochondria as a novel therapeutic target. This role of SEPN1 contributes to explain the fatigue and core lesions in skeletal muscle as well as the body composition abnormalities identified as part of the SEPN1-RM phenotype. Finally, these results point out to an unrecognized interplay between mitochondrial bioenergetics and ER homeostasis in skeletal muscle. They could therefore pave the way to the identification of biomarkers and therapeutic drugs for SEPN1-RM and for other disorders in which muscle ER-mitochondria cross-talk are impaired.

Dataset Information

An absence of nuclear lamins in keratinocytes leads to ichthyosis, defective epidermal barrier function, and intrusion of nuclear membranes and endoplasmic reticulum into the nuclear chromatin.

Publications

An absence of nuclear lamins in keratinocytes leads to ichthyosis, defective epidermal barrier function, and intrusion of nuclear membranes and endoplasmic reticulum into the nuclear chromatin.

Similar Datasets

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