A Novel Divergent Gene Transcription Paradigm-the Decisive, Brain-Specific, Neural |-Srgap2-Fam72a-| Master Gene Paradigm

Abstract

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.