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Neurofibromatosis type 1 alternative splicing is a key regulator of Ras/ERK signaling and learning behaviors in mice.

ABSTRACT: Appropriate activation of the Ras/extracellular signal-regulated kinase (ERK) protein signaling cascade within the brain is crucial for optimal learning and memory. One key regulator of this cascade is the Nf1 Ras GTPase activating protein (RasGAP), which attenuates Ras/ERK signaling by converting active Ras is bound to guanosine triphosphate, activating Ras into inactive Ras is bound to guanosine diphosphate, inactivating Ras. A previous study using embryonic stem cells and embryonic stem cell-derived neurons indicated that Nf1 RasGAP activity is modulated by the highly regulated alternative splicing of Nf1 exon 23a. In this study, we generated Nf123aIN/23aIN mice, in which the splicing signals surrounding Nf1 exon 23a were manipulated to increase exon inclusion. Nf123aIN/23aIN mice are viable and exon 23a inclusion approaches 100% in all tissues, including the brain, where the exon is normally almost completely skipped. Ras activation and phosphorylation of ERK1/2 downstream of Ras are both greatly increased in Nf123aIN/23aIN mouse brain lysates, confirming that exon 23a inclusion inhibits Nf1 RasGAP activity in vivo as it does in cultured cells. Consistent with the finding of altered Ras/ERK signaling in the brain, Nf123aIN/23aIN mice showed specific deficits in learning and memory compared with Nf1+/+ mice. Nf123aIN/23aIN mice performed poorly on the T-maze and Morris water maze tests, which measure short- and long-term spatial memory, respectively. In addition, Nf123aIN/23aIN mice showed abnormally elevated context-dependent fear and a diminished ability to extinguish a cued fear response, indicating defective associative fear learning. Therefore, the regulated alternative splicing of Nf1 is an important mechanism for fine-tuning Ras/ERK signaling as well as learning and memory in mice.

SUBMITTER: Nguyen HT

PROVIDER: S-EPMC5886178 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Neurofibromatosis type 1 alternative splicing is a key regulator of Ras/ERK signaling and learning behaviors in mice.

Nguyen Hieu T HT Hinman Melissa N MN Guo Xuan X Sharma Alok A Arakawa Hiroyuki H Luo Guangbin G Lou Hua H

Human molecular genetics 20171001 19

Appropriate activation of the Ras/extracellular signal-regulated kinase (ERK) protein signaling cascade within the brain is crucial for optimal learning and memory. One key regulator of this cascade is the Nf1 Ras GTPase activating protein (RasGAP), which attenuates Ras/ERK signaling by converting active Ras is bound to guanosine triphosphate, activating Ras into inactive Ras is bound to guanosine diphosphate, inactivating Ras. A previous study using embryonic stem cells and embryonic stem cell- ...[more]

PMID: 28934393

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Project description:BackgroundIn complex Metazoans a given gene frequently codes for multiple protein isoforms, through processes such as alternative splicing. Large scale functional annotation of these isoforms is a key challenge for functional genomics. This annotation gap is increasing with the large numbers of multi transcript genes being identified by technologies such as RNASeq. Furthermore attempts to characterise the functions of splicing in an organism are complicated by the difficulty in distinguishing functional isoforms from those produced by splicing errors or transcription noise. Tools to help prioritise candidate isoforms for testing are largely absent.ResultsIn this study we implement a Time-course Switch (TS) score for ranking isoforms by their likelihood of producing additional functions based on their developmental expression profiles, as reported by modENCODE. The TS score allows us to better investigate functional roles of different isoforms expressed in multi transcript genes. From this analysis, we find that isoforms with high TS scores have sequence feature changes consistent with more deterministic splicing and functional changes and tend to gain domains or whole exons which could carry additional functions. Furthermore these functions appear to be particularly important for essential regulatory roles, establishing functional isoform switching as key for regulatory processes. Based on the TS score we develop a Transcript Annotations Pipeline for Alternative Splicing (TAPAS) that identifies functional neighbourhoods of potentially interesting isoforms.ConclusionsWe have identified a subset of protein isoforms which appear to have high functional significance, particularly in regulation. This has been made possible through the development of novel methods that make use of transcript expression profiles. The methods and analyses we present here represent important first steps in the development of tools to address the near complete lack of isoform specific function annotation. In turn the tools allow us to better characterise the regulatory functions of alternative splicing in more detail.

Dataset Information

Neurofibromatosis type 1 alternative splicing is a key regulator of Ras/ERK signaling and learning behaviors in mice.

Publications

Neurofibromatosis type 1 alternative splicing is a key regulator of Ras/ERK signaling and learning behaviors in mice.

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