Cell cycle and cell fate interactions in neural development Federico Cremisi  , Anna Philpott y and Shin-ichi Ohnuma z Mechanisms coupling cell cycle and cell fate operate at different steps during neural development. Intrinsic factors control the cell proliferation of distinct brain regions and changes of cell fate competence, whereas components of the cell cycle machinery could play a major role in setting the appropriate timing of the generation of different cell types. Addresses  Scuola Normale Superiore/Dipartimento di Fisiologia e Biochimica, Sezione di Biologia Cellulare e dello Sviluppo, Universita ` di Pisa, Via Carducci 13, Ghezzano, Pisa, 56010, Italy e-mail: cremisi@dfb.unipi.it yz The Hutchinson/MRC Research Centre, Department of Oncology, University of Cambridge, Hills Road, Cambridge CB2 2XZ, UK y e-mail: ap113@hermes.cam.ac.uk z e-mail: so218@cam.ac.uk Current Opinion in Neurobiology 2003, 13:26–33 This review comes from a themed issue on Development Edited by Magdalena Go ¨ tz and Samuel L Pfaff 0959-4388/03/$ – see front matter ß 2003 Elsevier Science Ltd. All rights reserved. DOI 10.1016/S0959-4388(03)00005-9 Abbreviations bHLH basic helix-loop-helix Cdk cyclin-dependent kinase Cdki cyclin-dependent kinase inhibitor NEP neuroepithelial progenitors Rb retinoblastoma protein TF transcription factor Introduction A major requirement of the vertebrate neural develop- mental programme is the co-ordination of cell cycle regulation and cell fate determination. Many recent observations have highlighted functional cross-talk between molecules controlling these two processes. Key factors regulating cell cycle progression influence neural cell fate, whereas determination/differentiation factors have a role in regulating the cell cycle [1,2]. Although some of the molecular interactions and path- ways have been elucidated, there are still some important questions that remain unanswered. How is cell cycle progression controlled in specific embryonic cell compart- ments to allow for proper growth of different nervous structures? What are the molecular mechanisms that co- ordinate cell cycle progression and cell determination/ differentiation? How do the cell cycle machinery and determination/differentiation factors co-operate to achieve correct timing for the generation of the different cell types? Does the asymmetry of cell division of verte- brate neural progenitors play a role in selecting different neural cell fates? Recently, several patterning genes were found to control the cell proliferation rate of distinct central nervous system (CNS) structures, and dual function molecules have been described that couple cell cycle and cell fate. Finally, vertebrate genes that control the mode of cell division of neural progenitors, symmetric or asymmetric, have been described. In this review, we focus on intrinsic factors, here defined as intracellular genetic signals that influence a cell regardless of the environment. Among such factors, we consider cell cycle regulators and deter- mination/differentiation factors that control the co-ordi- nation of cell cycle and cell fate in the vertebrate nervous system. Intrinsic factors control cell proliferation of distinct embryonic neural regions Emerging evidence suggests that several patterning genes can control cell cycling in specific regions of the embryo, thus contributing to the differential growth of embryonic tissues and organs. Wnts and Sonic Hedgehog are examples of extrinsic cues that regulate the prolifera- tion rate in distinct neural embryonic regions [3,4], while also playing a role in neural induction and the patterning of the CNS. Transcription factors (TFs) that control early patterning of the CNS also support the cell cycle pro- gression of neural progenitors. In Xenopus anterior neural plate, high doses of the winged helix TF XBF-1 increase both the number of ectodermal cells devoted to a neural fate and their proliferation [5]. Similarly, the mouse Bf-1 gene controls the patterning and supports proliferation of the cells in the telencephalon, and the Bf-1 mutant mice show accordingly smaller telencephalic vesicles [6]. The homeobox TF Emx2, which specifies early dorsal tele- ncephalic identity and is necessary for proper develop- ment of cortical structures, supports clonal expansion of multipotent cortical progenitors in primary cultures with- out affecting cells of the basal telencephalon [7  ]. Finally, Rx1, Six3 and XOptx2 are necessary for eye formation and their expression is sufficient to drive retinal expansion [8–11]. In overexpression experiments, retinal over- growth is due to increased cell proliferation rather than to re-specification of non-neural tissue. Notably, Emx2, Rx1, Six3 and XOptx2 show a restricted regional compe- tence, as they can promote cell cycle progression of neural progenitors only in those regions where they are usually expressed. This suggests that co-factors may be required to interact with these TFs in a given developing region to control cell proliferation. This has been shown to be true 26 Current Opinion in Neurobiology 2003, 13:26–33 www.current-opinion.com