Age-related neurodegeneration and cognitive impairments of NRMT1 knockout mice are preceded by misregulation of RB and abnormal neural stem cell development

• Published in: Cell death & disease Vol. 12; no. 11; p. 1014
• Main Authors: Catlin, James P., Marziali, Leandro N., Rein, Benjamin, Yan, Zhen, Feltri, M. Laura, Schaner Tooley, Christine E.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 28.10.2021; Springer Nature B.V; Nature Publishing Group
• Subjects: 13/100; 13/51; 13/95; 14; 14/63; 631/378/2183/2182; 631/45/882; 64/60; Aging; Aging - pathology; Animals; Animals, Newborn; Antibodies; Apoptosis; Behavior, Animal; Biochemistry; Biomedical and Life Sciences; Cancer; Cell Biology; Cell Culture; Cell Cycle; Cell differentiation; Cerebral Ventricles - pathology; Cognitive ability; Cognitive Dysfunction - complications; Cognitive Dysfunction - genetics; Cognitive Dysfunction - pathology; Deoxyribonucleic acid; DNA; DNA damage; DNA methylation; DNA repair; Gene Expression Regulation; Gene regulation; Gene silencing; Glial Fibrillary Acidic Protein - metabolism; Hippocampus; Hippocampus - pathology; Hyperactivity; Immunology; Ki-67 Antigen - metabolism; Life Sciences; Maze Learning; Memory Disorders - complications; Methyltransferase; Methyltransferases - metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Mitosis; Neostriatum; Nerve Degeneration - complications; Nerve Degeneration - genetics; Nerve Degeneration - pathology; Neural stem cells; Neural Stem Cells - metabolism; Neural Stem Cells - pathology; Neurodegeneration; Neurogenesis; Neurons - metabolism; Neurons - pathology; Phenotypes; Phosphorylation; Retina; Retinoblastoma; Retinoblastoma protein; Retinoblastoma Protein - genetics; Retinoblastoma Protein - metabolism; RNA, Messenger - genetics; RNA, Messenger - metabolism; Spatial Memory; Stem Cell Niche; Stem cells; Ventricle (lateral)
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-021-04316-0

N-terminal methylation is an important posttranslational modification that regulates protein/DNA interactions and plays a role in many cellular processes, including DNA damage repair, mitosis, and transcriptional regulation. Our generation of a constitutive knockout mouse for the N-terminal methyltransferase NRMT1 demonstrated its loss results in severe developmental abnormalities and premature aging phenotypes. As premature aging is often accompanied by neurodegeneration, we more specifically examined how NRMT1 loss affects neural pathology and cognitive behaviors. Here we find that Nrmt1 −/− mice exhibit postnatal enlargement of the lateral ventricles, age-dependent striatal and hippocampal neurodegeneration, memory impairments, and hyperactivity. These morphological and behavior abnormalities are preceded by alterations in neural stem cell (NSC) development. Early expansion and differentiation of the quiescent NSC pool in Nrmt1 −/− mice is followed by its subsequent depletion and many of the resulting neurons remain in the cell cycle and ultimately undergo apoptosis. These cell cycle phenotypes are reminiscent to those seen with loss of the NRMT1 target retinoblastoma protein (RB). Accordingly, we find misregulation of RB phosphorylation and degradation in Nrmt1 −/− mice, and significant de-repression of RB target genes involved in cell cycle. We also identify novel de-repression of Noxa , an RB target gene that promotes apoptosis. These data identify Nα-methylation as a novel regulatory modification of RB transcriptional repression during neurogenesis and indicate that NRMT1 and RB work together to promote NSC quiescence and prevent neuronal apoptosis.