Subject(s)
Fetal Growth Retardation/diagnostic imaging , Progeria/diagnostic imaging , Ultrasonography, Prenatal , Cesarean Section , Facial Bones/diagnostic imaging , Facial Bones/embryology , Fetal Growth Retardation/therapy , Humans , Infant, Newborn , Infant, Premature , Infant, Premature, Diseases/pathology , Infant, Premature, Diseases/therapy , Male , Physical Examination , Progeria/embryology , Progeria/therapyABSTRACT
Hutchinson-Gilford progeria syndrome (HGPS) and restrictive dermopathy (RD) are two laminopathies caused by mutations leading to cellular accumulation of prelamin A or one of its truncated forms, progerin. One proposed mechanism for the more severe symptoms in patients with RD compared with HGPS is that higher levels of farnesylated lamin A are produced in RD. Here, we show evidence in support of that hypothesis. Overexpression of the most common progeroid lamin A mutation (LMNA c.1824C>T, p.G608G) during skin development results in a severe phenotype, characterized by dry scaly skin. At postnatal day 5 (PD5), progeroid animals showed a hyperplastic epidermis, disorganized sebaceous glands and an acute inflammatory dermal response, also involving the hypodermal fat layer. PD5 animals also showed an upregulation of multiple inflammatory response genes and an activated NF-kB target pathway. Careful analysis of the interfollicular epidermis showed aberrant expression of the lamin B receptor (LBR) in the suprabasal layer. Prolonged expression of LBR, in 14.06% of the cells, likely contributes to the observed arrest of skin development, clearly evident at PD4 when the skin had developed into single-layer epithelium in the wild-type animals while progeroid animals still had the multilayered appearance typical for skin at PD3. Suprabasal cells expressing LBR showed altered DNA distribution, suggesting the induction of gene expression changes. Despite the formation of a functional epidermal barrier and proven functionality of the gap junctions, progeroid animals displayed a greater rate of water loss as compared with wild-type littermates and died within the first two postnatal weeks.
Subject(s)
Embryo, Mammalian/metabolism , Lamin Type A/genetics , Mutation/genetics , Progeria/genetics , RNA Splicing/genetics , Skin/embryology , Skin/growth & development , Animals , Animals, Newborn , Biomarkers/metabolism , Cell Differentiation , Digestive System/pathology , Epidermis/embryology , Epidermis/pathology , Female , Gene Expression Regulation, Developmental , Humans , Inflammation/pathology , Lamin Type B/genetics , Lamin Type B/metabolism , Mice , Mice, Transgenic , NF-kappa B/metabolism , Phenotype , Progeria/embryology , Progeria/pathology , Receptors, Cytoplasmic and Nuclear/metabolism , Signal Transduction , Skin/pathology , Tight Junctions/metabolism , Up-Regulation/genetics , Water Loss, Insensible , Lamin B ReceptorABSTRACT
Although DNA damage is considered a driving force for aging, the nature of the damage that arises endogenously remains unclear. Replicative stress, a source of endogenous DNA damage, is prevented primarily by the ATR kinase. We have developed a mouse model of Seckel syndrome characterized by a severe deficiency in ATR. Seckel mice show high levels of replicative stress during embryogenesis, when proliferation is widespread, but this is reduced to marginal amounts in postnatal life. In spite of this decrease, adult Seckel mice show accelerated aging, which is further aggravated in the absence of p53. Together, these results support a model whereby replicative stress, particularly in utero, contributes to the onset of aging in postnatal life, and this is balanced by the replicative stress-limiting role of the checkpoint proteins ATR and p53.
