SIX homeoproteins were first described in Drosophila, where they participate in the Pax-Six-Eya-Dach (PSED) network with eyeless, eyes absent and dachsund to drive synergistically eye development through genetic and biochemical interactions. The role of the PSED network and SIX proteins in muscle formation in vertebrates was subsequently identified. Evolutionary conserved interactions with EYA and DACH proteins underlie the activity of SIX transcriptional complexes (STC) both during embryogenesis and in adult myofibers. Six genes are expressed throughout muscle development, in embryonic and adult proliferating myogenic stem cells and in fetal and adult post-mitotic myofibers, where SIX proteins regulate the expression of various categories of genes. In vivo, SIX proteins control many steps of muscle development, acting through feedforward mechanisms: in the embryo for myogenic fate acquisition through the direct control of Myogenic Regulatory Factors; in adult myofibers for their contraction/relaxation and fatigability properties through the control of genes involved in metabolism, sarcomeric organization and calcium homeostasis. Furthermore, during development and in the adult, SIX homeoproteins participate in the genesis and the maintenance of myofibers diversity.

六种同源蛋白最早在果蝇中描述，它们以无眼，无眼和腊肠的形式参与Pax-Six-Eya-Dach（PSED）网络，以通过遗传和生化相互作用协同驱动眼部发育。随后确定了PSED网络和SIX蛋白在脊椎动物肌肉形成中的作用。与EYA和DACH蛋白的进化保守相互作用是胚胎发生期间和成年肌纤维中SIX转录复合物（STC）活性的基础。六这些基因在整个肌肉发育过程中，在胚胎和成年增殖的成肌干细胞中以及在胎儿和成年有丝分裂后的肌纤维中表达，其中SIX蛋白调节各种基因的表达。在体内， SIX蛋白通过前馈机制起作用，控制肌肉发育的许多步骤：在胚胎中，通过直接控制肌源性调节因子来获得肌源性命运；通过控制与代谢，肌节组织和钙稳态有关的基因来控制成年肌纤维的收缩/松弛和易疲劳性。此外，在发育过程中和成年期，六种同源蛋白参与肌纤维多样性的发生和维持。