RESUMEN
Gene duplication is a major evolutionary force driving adaptation and speciation, as it allows for the acquisition of new functions and can augment or diversify existing functions. Here, we report a gene duplication event that yielded another outcome--the generation of antagonistic functions. One product of this duplication event--UPF3B--is critical for the nonsense-mediated RNA decay (NMD) pathway, while its autosomal counterpart--UPF3A--encodes an enigmatic protein previously shown to have trace NMD activity. Using loss-of-function approaches in vitro and in vivo, we discovered that UPF3A acts primarily as a potent NMD inhibitor that stabilizes hundreds of transcripts. Evidence suggests that UPF3A acquired repressor activity through simple impairment of a critical domain, a rapid mechanism that may have been widely used in evolution. Mice conditionally lacking UPF3A exhibit "hyper" NMD and display defects in embryogenesis and gametogenesis. Our results support a model in which UPF3A serves as a molecular rheostat that directs developmental events.
Asunto(s)
Desarrollo Embrionario , Genes Duplicados , Degradación de ARNm Mediada por Codón sin Sentido , Proteínas de Unión al ARN/metabolismo , Animales , Línea Celular Tumoral , Evolución Molecular , Gametogénesis , Células HeLa , Humanos , RatonesRESUMEN
NMD is a highly conserved pathway that degrades specific subsets of RNAs. There is increasing evidence for roles of NMD in development. In this commentary, we focus on spermatogenesis, a process dramatically impeded upon loss or disruption of NMD. NMD requires strict regulation for normal spermatogenesis, as loss of a newly discovered NMD repressor, UPF3A, also causes spermatogenic defects, most prominently during meiosis. We discuss the unusual evolution of UPF3A, whose paralog, UPF3B, has the opposite biochemical function and acts in brain development. We also discuss the regulation of NMD during germ cell development, including in chromatoid bodies, which are specifically found in haploid germ cells. The ability of NMD to coordinately degrade batteries of RNAs in a regulated fashion during development is akin to the action of transcriptional pathways, yet has the advantage of driving rapid changes in gene expression.
Asunto(s)
Evolución Biológica , Regulación de la Expresión Génica , Estabilidad del ARN , Espermatogénesis/genética , Testículo/fisiología , Animales , Diferenciación Celular/genética , Células Germinativas/citología , Células Germinativas/metabolismo , Humanos , Masculino , Degradación de ARNm Mediada por Codón sin Sentido , Unión Proteica , ARN Mensajero/genética , ARN Mensajero/metabolismo , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/metabolismo , Proteínas Represoras/genética , Proteínas Represoras/metabolismo , Especificidad por SustratoRESUMEN
The UPF3B-dependent branch of the nonsense-mediated RNA decay (NMD) pathway is critical for human cognition. Here, we examined the role of UPF3B in the olfactory system. Single-cell RNA-sequencing (scRNA-seq) analysis demonstrated considerable heterogeneity of olfactory sensory neuron (OSN) cell populations in wild-type (WT) mice, and revealed that UPF3B loss influences specific subsets of these cell populations. UPF3B also regulates the expression of a large cadre of antimicrobial genes in OSNs, and promotes the selection of specific olfactory receptor (Olfr) genes for expression in mature OSNs (mOSNs). RNA-seq and Ribotag analyses identified classes of mRNAs expressed and translated at different levels in WT and Upf3b-null mOSNs. Integrating multiple computational approaches, UPF3B-dependent NMD target transcripts that are candidates to mediate the functions of NMD in mOSNs were identified in vivo. Together, our data provides a valuable resource for the olfactory field and insights into the roles of NMD in vivo.