A Jacob/Nsmf Gene Knockout Results in Hippocampal Dysplasia and Impaired BDNF Signaling in Dendritogenesis

Jacob, the protein encoded by the Nsmf gene, is involved in synapto-nuclear signaling and docks an N-Methyl-D-Aspartate receptor (NMDAR)-derived signalosome to nuclear target sites like the transcription factor cAMP-response-element-binding protein (CREB). Several reports indicate that mutations in NSMF are related to Kallmann syndrome (KS), a neurodevelopmental disorder characterized by idiopathic hypogonadotropic hypogonadism (IHH) associated with anosmia or hyposmia. It has also been reported that a protein knockdown results in migration deficits of Gonadotropin-releasing hormone (GnRH) positive neurons from the olfactory bulb to the hypothalamus during early neuronal development. Here we show that mice that are constitutively deficient for the Nsmf gene do not present phenotypic characteristics related to KS. Instead, these mice exhibit hippocampal dysplasia with a reduced number of synapses and simplification of dendrites, reduced hippocampal long-term potentiation (LTP) at CA1 synapses and deficits in hippocampus-dependent learning. Brain-derived neurotrophic factor (BDNF) activation of CREB-activated gene expression plays a documented role in hippocampal CA1 synapse and dendrite formation. We found that BDNF induces the nuclear translocation of Jacob in an NMDAR-dependent manner in early development, which results in increased phosphorylation of CREB and enhanced CREB-dependent Bdnf gene transcription. Nsmf knockout (ko) mice show reduced hippocampal Bdnf mRNA and protein levels as well as reduced pCREB levels during dendritogenesis. Moreover, BDNF application can rescue the morphological deficits in hippocampal pyramidal neurons devoid of Jacob. Taken together, the data suggest that the absence of Jacob in early development interrupts a positive feedback loop between BDNF signaling, subsequent nuclear import of Jacob, activation of CREB and enhanced Bdnf gene transcription, ultimately leading to hippocampal dysplasia.

由Nsmf基因编码的Jacob蛋白参与突触-核信号转导，并可将N-甲基-D-天冬氨酸受体（NMDAR）衍生的信号小体锚定至转录因子cAMP反应元件结合蛋白（CREB）等核靶点。多项研究表明，NSMF基因突变与卡尔曼综合征（KS）相关——这是一种以特发性促性腺激素减退性性腺功能减退症（IHH）伴嗅觉缺失或嗅觉减退为特征的神经发育障碍。另有研究显示，在神经元发育早期，该蛋白的敲低会导致促性腺激素释放激素（GnRH）阳性神经元从嗅球向下丘脑的迁移出现缺陷。本研究发现，组成型缺失Nsmf基因的小鼠并未表现出与卡尔曼综合征相关的表型特征。相反，这些小鼠出现海马发育异常，具体表现为突触数量减少、树突结构简化，CA1突触处的海马长时程增强（LTP）水平降低，以及海马依赖型学习能力受损。脑源性神经营养因子（BDNF）对CREB激活的基因表达的调控作用，在海马CA1突触与树突形成中已有明确记载。本研究发现，在发育早期，BDNF可通过NMDAR依赖的方式诱导Jacob蛋白向细胞核转位，进而增加CREB的磷酸化水平，并增强CREB依赖的Bdnf基因转录。Nsmf基因敲除（ko）小鼠在树突发生过程中，海马BDNF的mRNA与蛋白水平以及磷酸化CREB（pCREB）的水平均出现降低。此外，施加BDNF可挽救缺失Jacob蛋白的海马锥体神经元的形态学缺陷。综上，本研究数据表明，发育早期Jacob蛋白的缺失会打断BDNF信号通路、Jacob蛋白后续核转位、CREB激活以及Bdnf基因转录增强之间的正反馈环路，最终导致海马发育异常。