Graduate School of Biomedical Science and Engineering, Hanyang University, 222 Wangsimni-ro, Seongdong-gu, Seoul, 133-791, Republic of Korea.
Department of Information Systems, College of Engineering, Hanyang University, 222 Wangsimni-ro, Seongdong-gu, Seoul, 133-791, Republic of Korea.
Mol Neurobiol. 2019 Aug;56(8):5891-5899. doi: 10.1007/s12035-019-1486-5. Epub 2019 Jan 26.
Brain development and repair largely depend on neural stem cells (NSCs). Here, we suggest that two genes, i.e., Srgap2 (SLIT-ROBO Rho GTPase-activating protein 2) and Fam72a (family with sequence similarity to 72, member A), constitute a single, NSC-specific, |-Srgap2-Fam72a-| master gene pair co-existing in reciprocal functional dependency. This gene pair has a dual, commonly used, intergenic region (IGR) promotor, which is a prerequisite in controlling human brain plasticity. We applied fluorescence cellular microscopy and fluorescence-activated cell sorting (FACS) to assess rat |-Srgap2-Fam72a-| master gene IGR promotor activity upon stimulation with two contrary growth factors: nerve growth factor (Ngf, a differentiation growth factor) and epidermal growth factor (Egf, a mitotic growth factor). We found that Ngf and Egf acted on the same IGR gene promotor element of the |-Srgap2-Fam72a-| master gene to mediate cell differentiation and proliferation, respectively. Ngf mediated Srgap2 expression and neuronal survival and differentiation while Egf activated Fam72a transcription and cell proliferation. Our data provide new insights into the specific regulation of the |-Srgap2-Fam72a-| master gene with its dual IGR promotor that controls two reverse-oriented functional-dependent genes located on opposite DNA strands. This structure represents a novel paradigm for controlling transcription of divergent genes in regulating NSC gene expression. This paradigm may allow for novel therapeutic approaches to restore or improve higher cognitive functions and cure cancers.
大脑发育和修复在很大程度上依赖于神经干细胞（NSCs）。在这里，我们提出两个基因，即 Srgap2（SLIT-ROBO Rho GTPase 激活蛋白 2）和 Fam72a（具有与 72 个序列相似性的家族成员 A），构成一个单一的、NSC 特异性的、|-Srgap2-Fam72a-|主基因对，共同存在于相互功能依赖关系中。这个基因对有一个双用途的、常见的基因间区（IGR）启动子，这是控制人类大脑可塑性的先决条件。我们应用荧光细胞显微镜和荧光激活细胞分选（FACS）技术来评估大鼠 |-Srgap2-Fam72a-|主基因 IGR 启动子活性，刺激物是两种相反的生长因子：神经生长因子（Ngf，一种分化生长因子）和表皮生长因子（Egf，一种有丝分裂生长因子）。我们发现，Ngf 和 Egf 作用于 |-Srgap2-Fam72a-|主基因的相同 IGR 基因启动子元件上，分别介导细胞分化和增殖。Ngf 介导 Srgap2 表达和神经元存活和分化，而 Egf 激活 Fam72a 转录和细胞增殖。我们的数据为 |-Srgap2-Fam72a-|主基因及其双 IGR 启动子的特异性调节提供了新的见解，该启动子控制位于相反 DNA 链上的两个反向功能相关基因。这种结构代表了一种控制 NSC 基因表达的、调节发散基因转录的新型范例。这种范例可能为恢复或改善高级认知功能和治疗癌症提供新的治疗方法。
