The E3 ubiquitin ligase skp2 regulates neural differentiation independent from the cell cycle

Using Xenopus as a model system, here we demonstrate that skp2 has an additional role in regulation of differentiation of primary neurons, the first neurons to differentiate in the neural plate. Xenopus skp2 shows a dynamic expression pattern in early embryonic neural tissue and depletion of skp2 results in generation of extra primary neurons. In contrast, over-expression of skp2 inhibits neurogenesis in a manner dependent on its ability to act as part of the SCFskp2 complex. Moreover, inhibition of neurogenesis by skp2 occurs upstream of the proneural gene encoding NeuroD and prior to cell cycle exit. We have previously demonstrated that the Xenopus cyclin dependent kinase inhibitor Xic1 is essential for primary neurogenesis at an early stage, and before these cells exit the cell cycle. We show that SCFskp2 degrades Xic1 in embryos and this contributes to the ability of skp2 to regulate neurogenesis.We conclude that the SCFskp2 complex has functions in the control of neuronal differentiation additional to its role in cell cycle regulation. Thus, it is well placed to be a co-ordinating factor regulating both cell proliferation and cell differentiation directly.Ubiquitin-mediated proteolysis has recently emerged as a central player in regulating destruction of proteins controlling cell fate determination, cell proliferation and cell differentiation [1,2]. Indeed, coordinating stability of proteins involved in these three processes is an efficient way for cells to decide to divide or to undergo differentiation.Polyubiquitination, which targets proteins for destruction, is brought about by a multi-enzyme cascade, typically involving E1 ubiquitin-activating enzymes, E2 ubiquitin-conjugating enzymes and E3 ubiquitin ligases [3]. Specificity for particular substrates resides in the E3 subunit, which is itself often a multi-subunit complex. The largest group of E3 ligases is the ring-finger domain family and within this family several so called SCF E3 ligases are known to