Cerebellum DOI 10.1007/s12311-015-0724-2 CONSENSUS PAPER Consensus Paper: Cerebellar Development Ketty Leto1,2 & Marife Arancillo3 & Esther B. E. Becker4 & Annalisa Buffo1,2 & Chin Chiang5 & Baojin Ding6 & William B. Dobyns 7,8 & Isabelle Dusart9,10 & Parthiv Haldipur7 & Mary E. Hatten11 & Mikio Hoshino12 & Alexandra L. Joyner13 & Masanobu Kano14 & Daniel L. Kilpatrick6 & Noriyuki Koibuchi15 & Silvia Marino16 & Salvador Martinez17 & Kathleen J. Millen7 & Thomas O. Millner16 & Takaki Miyata18 & Elena Parmigiani1,2 & Karl Schilling19 & Gabriella Sekerková20 & Roy V. Sillitoe3 & Constantino Sotelo21 & Naofumi Uesaka14 & Annika Wefers 22 & Richard J. T. Wingate23 & Richard Hawkes24 # The Author(s) 2015. This article is published with open access at Springerlink.com Abstract The development of the mammalian cerebellum is processes of cerebellar ontogenesis, highlighting the neuro- orchestrated by both cell-autonomous programs and inductive genic strategies used by developing progenitors, the genetic environmental influences. Here, we describe the main programs involved in cell fate specification, the progressive * Ketty Leto 10 Centre National de la Recherche Scientifique, CNRS, UMR8246, [email protected] INSERM U1130, Neuroscience Paris Seine, France, 75005 Paris, France 11 Laboratory of Developmental Neurobiology, The Rockefeller 1 Department of Neuroscience Rita Levi Montalcini, University of University, New York, NY 10065, USA Turin, via Cherasco 15, 10026 Turin, Italy 12 Department of Biochemistry and Cellular Biology, National Institute 2 Neuroscience Institute Cavalieri-Ottolenghi, University of Turin, of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Regione Gonzole 10, 10043 Orbassano, Torino, Italy Ogawa-Higashi, Kodaira, Tokyo 187-8502, Japan 3 Departments of Pathology & Immunology and Neuroscience, Baylor 13 Developmental Biology Program, Sloan Kettering Institute, New College of Medicine, Jan and Dan Duncan Neurological Research York, NY 10065, USA Institute of Texas Children’s Hospital, 1250 Moursund Street, Suite 14 Department of Neurophysiology, Graduate School of Medicine, The 1325, Houston, TX 77030, USA University of Tokyo, Tokyo 113-0033, Japan 4 Medical Research Council Functional Genomics Unit, Department of 15 Department of Integrative Physiology, Gunma University Graduate Physiology, Anatomy and Genetics, University of Oxford, School of Medicine, 3-39-22 Showa-machi, Oxford OX1 3PT, UK Maebashi, Gunma 371-8511, Japan 5 Department of Cell and Developmental Biology, Vanderbilt 16 Blizard Institute, Barts and The London School of Medicine and University Medical Center, 4114 MRB III, Nashville, TN 37232, Dentistry, Queen Mary University of London, 4 Newark Street, USA London E1 2AT, UK 6 Department of Microbiology and Physiological Systems and 17 Department Human Anatomy, IMIB-Arrixaca, University of Murcia, Program in Neuroscience, University of Massachusetts Medical Murcia, Spain School, 368 Plantation Street, Worcester, MA 01605-2324, USA 18 Department of Anatomy and Cell Biology, Nagoya University Graduate School of Medicine, Nagoya, Japan 7 Seattle Children’s Research Institute, Center for Integrative Brain Research, Seattle, WA, USA 19 Anatomie und Zellbiologie, Anatomisches Institut, Rheinische Friedrich-Wilhelms-Universität, Bonn, Germany 8 Department of Pediatrics, Genetics Division, University of Washington, Seattle, WA, USA 20 Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA 9 Sorbonne Universités, Université Pierre et Marie Curie Univ Paris 06, Institut de Biologie Paris Seine, France, 21 Institut de la Vision, UPMC Université de Paris 06, Paris 75012, 75005 Paris, France France Cerebellum changes of structural organization, and some of the better- (TH; L-triiodothyronine, known abnormalities associated with developmental disorders T3; L-tetraiodothyronine, of the cerebellum. thyroxine, T4) UBCs Unipolar brush cells Keywords Cerebellum . Progenitors . Purkinje cells . Specification . Differentiation Introduction (C. Sotelo) Abbreviations The work done on cerebellar development from the late nine- BG Bergmann glia teenth century until the 1970s provided substantial and signifi- CH Cerebellar hypoplasia cant information; however, it was only descriptive and barely CN Cerebellar nuclei addressed the mechanisms involved. Over the last two decades, CF Climbing fiber thanks to the technological revolution in molecular biology, our DWM Dandy Walker Malformation understanding of cerebellar development has drastically E Embryonic day (all timings are changed. We are now going through an exceptional period in mouse unless stated otherwise) our understanding of the mechanisms that underlie the complex ES Embryonic stem cell development of the cerebellum. An understanding of cell speci- EGL External granular layer fication regulated by the expression of region-specific combina- FGF Fibroblast growth factor tions of transcription factors or proneural genes, and the forma- GL Granular layer tion of synaptic circuits, seems within reach. GC Granule cell Ferdinando Rossi, a few months before his death, under- GCP Granule cell progenitors took the monumental task of writing a monograph on the HH Hamburger and Hamilton stage spectacular advances in our understanding of cerebellar devel- INs Interneurons opment achieved in the last 20 years. Sadly, Ferdinando died a IsO Isthmic organizer few months after beginning his monograph. This consensus JSRD Joubert syndrome and related paper, based on Ferdinando’s initial design, summarizes many disorders of these advances and is dedicated to his memory. MB Medulloblastoma The review comprises 18 brief sections, ranging from the ML Molecular layer early molecular specification of the cerebellar anlage to its ma- VZ Neuroepithelium of the ture architecture and pathology. It also includes information on ventricular zone of the 4th neurogenesis, mainly the specification and origins of neuronal ventricle and glial progenitors. An important part of the paper is devoted NTZ Nuclear transitory zone to Purkinje cells (PCs) as key neurons of the cerebellar cortex PF Parallel fiber responsible for the proliferation of granule cells (GCs) and the PIPs Pax-2+ IN progenitors establishment of Bcrude^ projection maps with extracerebellar P Postnatal day (all timings are afferent fibers. Finally, the biochemical heterogeneity of PCs mouse unless stated otherwise) allows for a cortical subdivision into distinct functional bands, PWM Prospective white matter a presumptive protomap for the development of circuit topogra- PC Purkinje cell phy (see in [1]). In this context, the problem of synapse elimi- PCPs Purkinje cell progenitors nation in the process of refinement and stabilization of climbing RL Rhombic lip fiber (CF) connections is also summarized. r1 Rhombomere 1 SCA Spinocerebellar ataxia The Molecular Specification of the Cerebellar Anlage: Thyroid hormone The Isthmic Organizer (S. Martinez) 22 Center for Neuropathology, Ludwig-Maximilians-University, The description of morphogenetic regulatory processes at spe- Munich, Germany cific locations of the developing neural primordium has led to 23 MRC Centre for Developmental Neurobiology, King’sCollege the concept of secondary organizers, which regulate the iden- London, London, UK tity and regional polarity of neighboring neuroepithelial re- 24 Department of Cell Biology & Anatomy and Hotchkiss Brain gions [2]. These organizers usually develop within the previ- Institute, Cumming School of Medicine, University of Calgary, ously broadly regionalized neuroectoderm with defined genet- Calgary T2N 4NI, AB, Canada ic boundaries. Their subsequent activity refines local neural Cerebellum Fig. 1 Topographical location of the mid-hindbrain boundary in the molecular maintenance of the isthmic region at E9.5. The table summa- E11.5 mouse embryo. a Dorsal view of an E11.5 mouse embryo illustrat- rizes the expression intensity and expression range of genes along the AP ing the isthmic constriction (isth) located between the mesencephalon and axis of the neural tube, focusing on the isthmus: the level of RNAm rhombomere 1 (r1). Rhombomeres r0 and r1, which give rise to the expression for each gene is represented by the number of (+) and the cerebellum, are highlighted in (a). The different color codes depict the color signifies the region of expression and the expression pattern (ho- expression pattern of the most important genes related to the morphoge- mogeneous or gradient), extending rostrally or caudally from the isthmus. netic activity and the capacity of the IsO. b Functional interactions (in- Tel telencephalon, Di diencephalon, Mes mesencephalon. Modified from duction/inhibition) of genes that, together with Fgf8, are involved in the [4] identities along the anteroposterior or dorsoventral axes, thus factors does not primarily affect the activation of Fgf8 expres- regionalizing the anterior neural plate and neural tube [3, 4]. sion [13, 14]. Other genes expressed at early stages across the The isthmic constriction of the neural tube contains the prospective MHB, such as Pax-2 and Iroquas (Irxs), seem also isthmic organizer (IsO; Fig. 1a), which provides structural to be required for the expression of Otx2, Gbx2,andFgf8 and polarity to the adjoining regions and orchestrates the complex the proper formation of the mesencephalic and cellular diversity of the mesencephalon (rostrally) and the cer- rhombencephalic vesicles. Moreover, FGF8 signaling may ebellum (caudally;