RESUMEN
The human 22q11.2 chromosomal deletion is one of the strongest identified genetic risk factors for schizophrenia. Although the deletion spans a number of known genes, the contribution of each of these to the 22q11.2 deletion syndrome (DS) is not known. To investigate the effect of individual genes within this interval on the pathophysiology associated with the deletion, we analyzed their role in sleep, a behavior affected in virtually all psychiatric disorders, including the 22q11.2 DS. We identified the gene LZTR1 (night owl, nowl) as a regulator of night-time sleep in Drosophila. In humans, LZTR1 has been associated with Ras-dependent neurological diseases also caused by Neurofibromin-1 (Nf1) deficiency. We show that Nf1 loss leads to a night-time sleep phenotype nearly identical to that of nowl loss and that nowl negatively regulates Ras and interacts with Nf1 in sleep regulation. Furthermore, nowl is required for metabolic homeostasis, suggesting that LZTR1 may contribute to the genetic susceptibility to obesity associated with the 22q11.2 DS. Knockdown of nowl or Nf1 in GABA-responsive sleep-promoting neurons elicits the sleep phenotype, and this defect can be rescued by increased GABAA receptor signaling, indicating that Nowl regulates sleep through modulation of GABA signaling. Our results suggest that nowl/LZTR1 may be a conserved regulator of GABA signaling important for normal sleep that contributes to the 22q11.2 DS.
Asunto(s)
Síndrome de Deleción 22q11/genética , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas de Drosophila/genética , Neuronas GABAérgicas/metabolismo , Neurofibromina 1/genética , Esquizofrenia/genética , Sueño/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Animales , Drosophila , Proteínas de Drosophila/metabolismo , Neuronas GABAérgicas/fisiología , Humanos , Neurofibromina 1/metabolismo , Receptores de GABA-A/metabolismo , Factores de Transcripción/genéticaRESUMEN
The human 1q21.1 deletion of ten genes is associated with increased risk of schizophrenia. This deletion involves the ß-subunit of the AMP-activated protein kinase (AMPK) complex, a key energy sensor in the cell. Although neurons have a high demand for energy and low capacity to store nutrients, the role of AMPK in neuronal physiology is poorly defined. Here we show that AMPK is important in the nervous system for maintaining neuronal integrity and for stress survival and longevity in Drosophila. To understand the impact of this signaling system on behavior and its potential contribution to the 1q21.1 deletion syndrome, we focused on sleep, an important role of which is proposed to be the reestablishment of neuronal energy levels that are diminished during energy-demanding wakefulness. Sleep disturbances are one of the most common problems affecting individuals with psychiatric disorders. We show that AMPK is required for maintenance of proper sleep architecture and for sleep recovery following sleep deprivation. Neuronal AMPKß loss specifically leads to sleep fragmentation and causes dysregulation of genes believed to play a role in sleep homeostasis. Our data also suggest that AMPKß loss may contribute to the increased risk of developing mental disorders and sleep disturbances associated with the human 1q21.1 deletion.
Asunto(s)
Proteínas Quinasas Activadas por AMP/genética , Anomalías Múltiples/enzimología , Anomalías Múltiples/genética , Megalencefalia/enzimología , Megalencefalia/genética , Neuronas/enzimología , Esquizofrenia/enzimología , Esquizofrenia/genética , Sueño/genética , Sueño/fisiología , Proteínas Quinasas Activadas por AMP/antagonistas & inhibidores , Proteínas Quinasas Activadas por AMP/deficiencia , Animales , Deleción Cromosómica , Cromosomas Humanos Par 1/enzimología , Cromosomas Humanos Par 1/genética , Proteínas de Drosophila/deficiencia , Proteínas de Drosophila/genética , Drosophila melanogaster/enzimología , Drosophila melanogaster/genética , Femenino , Técnicas de Silenciamiento del Gen , Predisposición Genética a la Enfermedad , Humanos , Aprendizaje/fisiología , Longevidad/genética , Longevidad/fisiología , Masculino , Modelos Animales , Neuronas/citología , Factores de Riesgo , Transducción de Señal , Trastornos del Sueño-Vigilia/enzimología , Trastornos del Sueño-Vigilia/genéticaRESUMEN
In adult zebrafish, relatively quiescent progenitor cells show lesion-induced generation of motor neurons. Developmental motor neuron generation from the spinal motor neuron progenitor domain (pMN) sharply declines at 48â hours post-fertilisation (hpf). After that, mostly oligodendrocytes are generated from the same domain. We demonstrate here that within 48â h of a spinal lesion or specific genetic ablation of motor neurons at 72â hpf, the pMN domain reverts to motor neuron generation at the expense of oligodendrogenesis. By contrast, generation of dorsal Pax2-positive interneurons was not altered. Larval motor neuron regeneration can be boosted by dopaminergic drugs, similar to adult regeneration. We use larval lesions to show that pharmacological suppression of the cellular response of the innate immune system inhibits motor neuron regeneration. Hence, we have established a rapid larval regeneration paradigm. Either mechanical lesions or motor neuron ablation is sufficient to reveal a high degree of developmental flexibility of pMN progenitor cells. In addition, we show an important influence of the immune system on motor neuron regeneration from these progenitor cells.