The family of KHDRBS protein (KH Domain-containing, RNA Binding, and Signal transduction associated protein), is characterized by the GSG (GRP33/SAM68/GLD-1) domain, also named STAR domain, which includes a single KH domain flanked by the conserved N-terminal QUA1 and C-terminal QUA2 (Di Fruscio et al., 1999; Lukong and Richard, 2003). KHDRBS proteins bind RNA through their KH domains, and participate in signal transduction (Frisone et al., 2015; Ehrmann et al., 2016). In nematodes, GLD-1, the ortholog of KHDRBS, was found to be localized in the germ cell cytoplasm, and indispensable for oogenesis and meiotic prophase progression, while it shows little roles in the male germ line or soma, although it can stimulate sex determination of males in the hermaphrodite germ line (Jones and Schedl, 1995; Lee and Schedl, 2001, 2010). In contrast, NSR, the ortholog of KHDRBS of fruit fly, was found to be predominantly localized in the nuclei of primary spermatocytes, and necessary for male reproduction by regulating some male fertility genes (Ding et al., 2010). In vertebrates, there are three members of KHDRBS, KHDRBS1 (also called Sam68), KHDRBS2 (also called SLM1), and KHDRBS3 (also called SLM2) which share many features such as RNA binding and signal transduction. Interestingly, khdrbs1 knockout mice showed impaired fertility in males as a result of mRNA translational regulation defect during spermiogenesis (Paronetto et al., 2009; Ehrmann and Elliott, 2010; Frisone et al., 2015), and KHDRBS3 was also involved in spermatogenesis via directly binding to the genes essential for male gametogenesis (Zhang et al., 2009). This function of KHDRBS1 and KHDRBS3 in mice is apparently analogous to their invertebrate orthologs GLD-1 and NSR in term of regulation of gametogenesis. On the contrary, the three members of vertebrate khdrbs family appear to be expressed more specifically in the brain. In mouse, khdrbs1 and khdrbs3 were predominantly expressed in the brain and testis, but khdrbs2 was exclusively expressed in the brain (Ehrmann et al., 2016). Moreover, although khdrbs1 KO male mice showed male infertility, behavioral deficits and poor motor control (Ehrmann et al., 2013), khdrbs2 KO mice as well as khdrbs1 and khdrbs2 double KO mice both exhibited defects in cerebellar morphogenesis (Iijima et al., 2014), and khdrbs3 KO mice displayed synaptic plasticity and behavioral defects (Traunmüller et al., 2016). These data together suggest that khdrbs gene family, as a member of genetic toolkit, may be linked to vertebrate brain development. However, the evolutionary relationship between khdrbs gene family and vertebrate brain development is still a mystery.