科研之友
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摘要
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 Nf1(23aIN/23aIN) mice, in which the splicing signals surrounding Nf1 exon 23a were manipulated to increase exon inclusion. Nf1(23aIN/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 downstreamof Ras are both greatly increased in Nf1(23aIN/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, Nf1(23aIN/23aIN) mice showed specific deficits in learning and memory compared with Nf1(+/+) mice. Nf1(23aIN/23aIN) mice performed poorly on the T-maze and Morris water maze tests, which measure short-and long-termspatial memory, respectively. In addition, Nf1(23aIN/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.
- 出版日期2017-10-1
