RESUMEN
In the United States, it is now estimated that 6.7 million people over the age of 65 are afflicted by Alzheimer's disease (AD), over 1 million people are living with Parkinson's disease (PD), and over 200 000 have or are at risk for developing Huntington's disease (HD). All three of these neurodegenerative diseases result in the ultimate death of distinct neuronal subtypes, and it is widely thought that age-related damage is the single biggest contributing factor to this neuronal death. However, recent studies are now suggesting that developmental defects during early neurogenesis could also play a role in the pathology of neurodegenerative diseases. Loss or overexpression of proteins associated with HD, PD, and AD also result in embryonic phenotypes but whether these developmental defects slowly unmask over time and contribute to age-related neurodegeneration remains highly debated. Here, we discuss known links between embryonic neurogenesis and neurodegenerative disorders (including common signaling pathways), potential compensatory mechanisms that could delay presentation of neurodegenerative disorders, and the types of model systems that could be used to study these links in vivo.
Asunto(s)
Enfermedades Neurodegenerativas , Neurogénesis , Humanos , Enfermedades Neurodegenerativas/metabolismo , Animales , Transducción de Señal , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/genética , Enfermedad de Huntington/metabolismo , Enfermedad de Huntington/patología , Enfermedad de Huntington/genética , Neuronas/metabolismo , Enfermedad de Alzheimer/metabolismoRESUMEN
The methyltransferase-like (METTL) family is a diverse group of methyltransferases that can methylate nucleotides, proteins, and small molecules. Despite this diverse array of substrates, they all share a characteristic seven-beta-strand catalytic domain, and recent evidence suggests many also share an important role in stem cell biology. The most well characterized family members METTL3 and METTL14 dimerize to form an N6-methyladenosine (m6A) RNA methyltransferase with established roles in cancer progression. However, new mouse models indicate that METTL3/METTL14 are also important for embryonic stem cell (ESC) development and postnatal hematopoietic and neural stem cell self-renewal and differentiation. METTL1, METTL5, METTL6, METTL8, and METTL17 also have recently identified roles in ESC pluripotency and differentiation, while METTL11A/11B, METTL4, METTL7A, and METTL22 have been shown to play roles in neural, mesenchymal, bone, and hematopoietic stem cell development, respectively. Additionally, a variety of other METTL family members are translational regulators, a role that could place them as important players in the transition from stem cell quiescence to differentiation. Here we will summarize what is known about the role of METTL proteins in stem cell differentiation and highlight the connection between their growing importance in development and their established roles in oncogenesis.
Asunto(s)
Metiltransferasas , Neoplasias , Ratones , Animales , Metiltransferasas/genética , Metiltransferasas/metabolismo , ARN/metabolismo , Células Madre Embrionarias , Diferenciación Celular/genética , Biología , Neoplasias/genética , Neoplasias/metabolismoRESUMEN
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.
Asunto(s)
Envejecimiento/patología , Disfunción Cognitiva/complicaciones , Metiltransferasas/metabolismo , Degeneración Nerviosa/complicaciones , Células-Madre Neurales/metabolismo , Proteína de Retinoblastoma/genética , Animales , Animales Recién Nacidos , Apoptosis , Conducta Animal , Ciclo Celular , Ventrículos Cerebrales/patología , Disfunción Cognitiva/genética , Disfunción Cognitiva/patología , Regulación de la Expresión Génica , Proteína Ácida Fibrilar de la Glía/metabolismo , Hipocampo/patología , Antígeno Ki-67/metabolismo , Aprendizaje por Laberinto , Trastornos de la Memoria/complicaciones , Ratones Endogámicos C57BL , Ratones Noqueados , Degeneración Nerviosa/genética , Degeneración Nerviosa/patología , Células-Madre Neurales/patología , Neuronas/metabolismo , Neuronas/patología , ARN Mensajero/genética , ARN Mensajero/metabolismo , Proteína de Retinoblastoma/metabolismo , Memoria Espacial , Nicho de Células MadreRESUMEN
The N-terminal methyltransferase NRMT1 is an important regulator of protein/DNA interactions and plays a role in many cellular processes, including mitosis, cell cycle progression, chromatin organization, DNA damage repair, and transcriptional regulation. Accordingly, loss of NRMT1 results in both developmental pathologies and oncogenic phenotypes. Though NRMT1 plays such important and diverse roles in the cell, little is known about its own regulation. To better understand the mechanisms governing NRMT1 expression, we first identified its predominant transcriptional start site and minimal promoter region with predicted transcription factor motifs. We then used a combination of luciferase and binding assays to confirm CREB1 as the major regulator of NRMT1 transcription. We tested which conditions known to activate CREB1 also activated NRMT1 transcription, and found CREB1-mediated NRMT1 expression was increased during recovery from serum starvation and muscle cell differentiation. To determine how NRMT1 expression affects myoblast differentiation, we used CRISPR/Cas9 technology to knock out NRMT1 expression in immortalized C2C12 mouse myoblasts. C2C12 cells depleted of NRMT1 lacked Pax7 expression and were unable to proceed down the muscle differentiation pathway. Instead, they took on characteristics of C2C12 cells that have transdifferentiated into osteoblasts, including increased alkaline phosphatase and type I collagen expression and decreased proliferation. These data implicate NRMT1 as an important downstream target of CREB1 during muscle cell differentiation.