RESUMEN
Injured axons must regenerate to restore nervous system function, and regeneration is regulated in part by external factors from non-neuronal tissues. Many of these extrinsic factors act in the immediate cellular environment of the axon to promote or restrict regeneration, but the existence of long-distance signals regulating axon regeneration has not been clear. Here we show that the Rab GTPase rab-27 inhibits regeneration of GABAergic motor neurons in C. elegans through activity in the intestine. Re-expression of RAB-27, but not the closely related RAB-3, in the intestine of rab-27 mutant animals is sufficient to rescue normal regeneration. Several additional components of an intestinal neuropeptide secretion pathway also inhibit axon regeneration, including NPDC1/cab-1, SNAP25/aex-4, KPC3/aex-5, and the neuropeptide NLP-40, and re-expression of these genes in the intestine of mutant animals is sufficient to restore normal regeneration success. Additionally, NPDC1/cab-1 and SNAP25/aex-4 genetically interact with rab-27 in the context of axon regeneration inhibition. Together these data indicate that RAB-27-dependent neuropeptide secretion from the intestine inhibits axon regeneration, and point to distal tissues as potent extrinsic regulators of regeneration.
Asunto(s)
Axones/fisiología , Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/fisiología , Neuronas GABAérgicas/fisiología , Intestinos/metabolismo , Regeneración , Proteínas de Unión al GTP rab/metabolismo , Proteínas rab27 de Unión a GTP/metabolismo , Animales , Proteínas de Caenorhabditis elegans/genética , Transducción de Señal , Vesículas Sinápticas/metabolismo , Proteínas de Unión al GTP rab/genética , Proteínas rab27 de Unión a GTP/genéticaRESUMEN
Activity of the RNA ligase RtcB has only two known functions: tRNA ligation after intron removal and XBP1 mRNA ligation during activation of the unfolded protein response. Here, we show that RtcB acts in neurons to inhibit axon regeneration after nerve injury. This function of RtcB is independent of its basal activities in tRNA ligation and the unfolded protein response. Furthermore, inhibition of axon regeneration is independent of the RtcB cofactor archease. Finally, RtcB is enriched at axon termini after nerve injury. Our data indicate that neurons have co-opted an ancient RNA modification mechanism to regulate specific and dynamic functions and identify neuronal RtcB activity as a critical regulator of neuronal growth potential.
Asunto(s)
Aminoacil-ARNt Sintetasas/metabolismo , Axones/fisiología , Proteínas de Caenorhabditis elegans/metabolismo , Regeneración Nerviosa , ARN Ligasa (ATP)/metabolismo , ARN de Helminto/metabolismo , Aminoacil-ARNt Sintetasas/genética , Animales , Animales Modificados Genéticamente , Axones/metabolismo , Axotomía/métodos , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/fisiología , Proteínas de Caenorhabditis elegans/genética , Proteínas Luminiscentes/genética , Proteínas Luminiscentes/metabolismo , Microscopía Fluorescente , Mutación , Neuronas/metabolismo , Neuronas/fisiología , ARN Ligasa (ATP)/genética , ARN de Helminto/genética , ARN de Transferencia/genética , ARN de Transferencia/metabolismoRESUMEN
Estrogen-receptor alpha (ERα) neurons in the ventrolateral region of the ventromedial hypothalamus (VMHVL) control an array of sex-specific responses to maximize reproductive success. In females, these VMHVL neurons are believed to coordinate metabolism and reproduction. However, it remains unknown whether specific neuronal populations control distinct components of this physiological repertoire. Here, we identify a subset of ERα VMHVL neurons that promotes hormone-dependent female locomotion. Activating Nkx2-1-expressing VMHVL neurons via pharmacogenetics elicits a female-specific burst of spontaneous movement, which requires ERα and Tac1 signaling. Disrupting the development of Nkx2-1(+) VMHVL neurons results in female-specific obesity, inactivity, and loss of VMHVL neurons coexpressing ERα and Tac1. Unexpectedly, two responses controlled by ERα(+) neurons, fertility and brown adipose tissue thermogenesis, are unaffected. We conclude that a dedicated subset of VMHVL neurons marked by ERα, NKX2-1, and Tac1 regulates estrogen-dependent fluctuations in physical activity and constitutes one of several neuroendocrine modules that drive sex-specific responses.
Asunto(s)
Receptor alfa de Estrógeno/metabolismo , Locomoción/genética , Proteínas Nucleares/biosíntesis , Obesidad/metabolismo , Taquicininas/genética , Factores de Transcripción/biosíntesis , Animales , Receptor alfa de Estrógeno/genética , Estrógenos/metabolismo , Femenino , Ratones , Neuronas/metabolismo , Neuronas/patología , Proteínas Nucleares/genética , Obesidad/genética , Obesidad/fisiopatología , Caracteres Sexuales , Taquicininas/metabolismo , Factor Nuclear Tiroideo 1 , Factores de Transcripción/genética , Núcleo Hipotalámico Ventromedial/metabolismo , Núcleo Hipotalámico Ventromedial/patologíaRESUMEN
Invertebrate model systems are powerful tools for studying human disease owing to their genetic tractability and ease of screening. We conducted a mosaic genetic screen of lethal mutations on the Drosophila X chromosome to identify genes required for the development, function, and maintenance of the nervous system. We identified 165 genes, most of whose function has not been studied in vivo. In parallel, we investigated rare variant alleles in 1,929 human exomes from families with unsolved Mendelian disease. Genes that are essential in flies and have multiple human homologs were found to be likely to be associated with human diseases. Merging the human data sets with the fly genes allowed us to identify disease-associated mutations in six families and to provide insights into microcephaly associated with brain dysgenesis. This bidirectional synergism between fly genetics and human genomics facilitates the functional annotation of evolutionarily conserved genes involved in human health.