br Acknowledgements This work was supported by

Acknowledgements This work was supported by the National Institute of Neurologic Disorders and Stroke (U54 HD061222, 1K23 NS107646-01, and 1K12NS089417-01), Rocky Mountain Rett Association, International Foundation for CDKL5 Research, the Ponzio Family Chair in Neurology Research, and NHMRC Senior Research Fellowship (#1117105). Drs. Walter E. Kaufmann and Sumit Parikh also participated in data collection by the International Foundation for CDKL5 Research Centers of Excellence.
Introduction Plant growth and development are governed by E-4031 strictly, through regulating the process of cell differentiation, cell division and cell growth. Cell cycle is a coordinated cyclic alteration of discrete phases G1, S, G2 and M, and complex regulatory networks of cell-cycle control system are involved in dominating the progression of DNA replication, DNA repair, mitosis, and cell growth, etc. (Alberts et al., 2008; Lents and Baldassare, 2016). Since cell division was firstly observed in the early 1900s, the molecular mechanisms of cell-cycle control were gradually uncovered (Lents and Baldassare, 2016; Nasmyth, 2001). The landmarks of cell cycle researches were cyclin and cyclin dependent kinase (CDK) characterization, which were granted the 2001 Nobel Prize in Physiology or Medicine (Gutierrez, 2016; Nasmyth, 2001). With the improvement of researches, as well as the application of genome sequencing, RNA sequencing and proteomic techniques, numerous cyclin and CDK related genes or proteins were isolated and identified (Bulankova et al., 2013; Flaishman et al., 2015; Lents and Baldassare, 2016; Vandepoele et al., 2002; Zhang et al., 2014). In the cell-cycle system, cyclins are important and positive regulators for CDK activities, which undergo a cycle of synthesis and degradation during each cell cycle (Alberts et al., 2008; Lents and Baldassare, 2016). The first plant cyclin was identified from carrot and soybean (Hata et al., 1991), then numerous cyclins were isolated and identified (Menges et al., 2005; Wang et al., 2004; Zhang et al., 2014). Based on conserved sequences and biological functions, cyclins were defined into 10 classes in the flowering plants, such as A, B, C, D, H, L, T, U, SDS, and J18 types (Wang et al., 2004; Zhang et al., 2014). However, cyclins are mainly expressed in G1- and M-phase. M-cyclins, including A- and B-type cyclins, are relatively stable and promote cell division, while G1-cyclins, such as C- and D-type cyclins, among others, subsist for a temporary time and help cells into S-phase (Zhang et al., 2014). Cyclins do not possess activation activity, but act only in complex with their partners, CDKs, to induce conformational change (Alberts et al., 2008; Lents and Baldassare, 2016; Ren et al., 2018). Unlike cyclins, CDKs are less divergent in eukaryotes (Lents and Baldassare, 2016; Vandepoele et al., 2002). CDKs contain an ATP-binding site, a cyclin-binding domain, and one or more phospho-regulatory sites (Lents and Baldassare, 2016). Arabidopsis CDKs were clustered into eight classes, including CDKA to CDKG, and CDK-like kinases (CKLs, Menges et al., 2005). CDKAs were reported to regulate G1/S and G2/M transitions, while CDKBs control G2/M checkpoint (Menges et al., 2005; Pokora et al., 2018). CDKCs and CDKEs might regulate transcription by phosphorylation or as a component of the RNA polymerase II holoenzyme; CDKDs and CDKFs are CDK-activating kinases, which catalyze activating phosphorylation of other CDKs; CDKGs are implicated in controlling homologous chromosome pairing and male meiosis; and CKLs are distinct phylogenetic clades from other CDKs, which their biological functions are still unclear (Inagaki and Umeda, 2011; Menges et al., 2005; Tank and Thaker, 2011; Zheng et al., 2014). Fruits are specialized organs that protect ovules and seeds, promote mature seed dispersal, and provide additional food and nutritional source. Researchers and breeders therefore pay much attention to fruit quality and yield (Ariizumi et al., 2013; Azzi et al., 2015; Mu et al., 2017; Xie et al., 2018). Final fruit size and mass are key factors for fruit yield, and most are likely determined by cell number and cell volume. Larger fruits contain more cells or larger cell volume, due to longer period for cell division or cell expansion (Ariizumi et al., 2013; Bertin et al., 2003; Colle et al., 2017; Mu et al., 2017; Okello et al., 2015). As mentioned before, cell proliferation is precisely controlled by regulatory mechanisms of cell cycle, and the information concerning cell cycle-related genes and its regulation mechanisms for fruit growth have been limited, mainly focused on Arabidopsis, tomato, apple and cucumber (Azzi et al., 2015; Colle et al., 2017; Malladi and Johnson, 2011; Menges et al., 2005).