Department of Neurobiology and Behavior, State University of New York, Stony Brook, Stony Brook, New York 11794, USA.
J Neurosci. 2010 Jul 7;30(27):9199-208. doi: 10.1523/JNEUROSCI.0605-10.2010.
Neuregulin 1 (NRG1) signaling is critical to various aspects of neuronal development and function. Among different NRG1 isoforms, the type III isoforms of NRG1 are unique in their ability to signal via the intracellular domain after gamma-secretase-dependent intramembranous processing. However, the functional consequences of type III NRG1 signaling via its intracellular domain are mostly unknown. In this study, we have identified mutations within type III NRG1 that disrupt intramembranous proteolytic processing and abolish intracellular domain signaling. In particular, substitutions at valine 321, previously linked to schizophrenia risks, result in NRG1 proteins that fail to undergo gamma-secretase-mediated nuclear localization and transcriptional activation. Using processing-defective mutants of type III NRG1, we demonstrate that the intracellular domain signaling is specifically required for NRG1 regulation of the growth and branching of cortical dendrites but not axons. Consistent with the role of type III NRG1 signaling via the intracellular domain in the initial patterning of cortical dendrites, our findings from pharmacological and genetic studies indicate that type III NRG1 functions in dendritic development independent of ERBB kinase activity. Together, these results support the proposal that aberrant intramembranous processing and defective signaling via the intracellular domain of type III NRG1 impair a subset of NRG1 functions in cortical development and contribute to abnormal neuroconnectivity implicated in schizophrenia.
神经调节蛋白 1（NRG1）信号对于神经元发育和功能的各个方面都至关重要。在不同的 NRG1 同种型中，NRG1 的 III 型同种型在经过 γ-分泌酶依赖性跨膜加工后通过细胞内结构域进行信号传递的能力是独特的。然而，III 型 NRG1 通过其细胞内结构域进行信号传递的功能后果在很大程度上尚不清楚。在这项研究中，我们已经鉴定出 III 型 NRG1 中的突变，这些突变会破坏跨膜蛋白水解加工并消除细胞内结构域信号传递。特别是，以前与精神分裂症风险相关的缬氨酸 321 的取代导致 NRG1 蛋白无法进行 γ-分泌酶介导的核定位和转录激活。使用 III 型 NRG1 的加工缺陷突变体，我们证明细胞内结构域信号传递对于 NRG1 调节皮质树突的生长和分支是特异性必需的，但对于轴突则不是。与 III 型 NRG1 通过细胞内结构域进行信号传递在皮质树突初始模式形成中的作用一致，我们的药理学和遗传学研究结果表明，III 型 NRG1 独立于 ERBB 激酶活性在树突发育中发挥作用。总之，这些结果支持这样的假设，即 III 型 NRG1 的跨膜加工异常和细胞内结构域信号传递缺陷会损害 NRG1 在皮质发育中的一部分功能，并导致精神分裂症中涉及的异常神经连接。
