The Cerebellum, K. Leto

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The Cerebellum, K. Leto

The Cerebellum, October 2015

Consensus paper: cerebellar development
in memory of Ferdinando Rossi

Ketty Leto 1,2* , Marife Arancillo 3 , Esther B.E. Becker 4 , Annalisa Buffo 1,2 , Chin Chiang 5 , Baojin Ding 6 , William B. Dobyns 7,8 , Isabelle Dusart 9,10 , Parthiv Haldipur 7 , Mary E. Hatten 11 , Mikio Hoshino 12 , Alexandra L. Joyner 13 , Masanobu Kano 14 , Daniel L. Kilpatrick 6 , Noriyuki Koibuchi 15 , Silvia Marino 16 , Salvador Martinez 17 , Kathleen J. Millen 7 , Thomas O. Millner 16 , Takai Miyata 18 , Elena Parmigiani 1,2 , Karl Schilling 19 , Gabriella Sekerková 20 , Roy V. Sillitoe 3 , Constantino Sotelo 21 , Naofumi Uesaka 14 , Annika Wefers 22 , Richard JT Wingate 23 , Richard Hawkes 24

The development of the mammalian cerebellum is orchestrated by both cell-autonomous programs and inductive environmental influences. Here, we describe the main processes of cerebellar ontogenesis, highlighting the neurogenic strategies used by developing progenitors, the genetic programs involved in cell fate specification, the progressive changes of structural organization, and some of the better-known abnormalities associated with developmental disorders of the cerebellum.


Introduction (C. Sotelo)
The work done on cerebellar development from the late nineteenth century until the 1970s provided substantial and significant information; however, it was only descriptive and barely addressed the mechanisms involved. Over the last two decades, thanks to the technological revolution in molecular biology, our understanding of cerebellar development has drastically changed.

We are now going through an exceptional period in our understanding of the mechanisms that underlie the complex development of the cerebellum. An understanding of cell specification regulated by the expression of region-specific combinations of transcription factors or proneural genes, and the formation of synaptic circuits, seems within reach.

Ferdinando Rossi, a few months before his death, undertook the monumental task of writing a monograph on the spectacular advances in our understanding of cerebellar development achieved in the last 20 years. Sadly, Ferdinando died a few months after beginning his monograph. This consensus paper, based on Ferdinando’s initial design, summarizes many of these advances and is dedicated to his memory.

The review comprises 18 brief sections, ranging from the early molecular specification of the cerebellar anlage to its mature architecture and pathology. It also includes information on neurogenesis, mainly the specification and origins of neuronal and glial progenitors.

An important part of the paper is devoted to Purkinje cells (PCs) as key neurons of the cerebellar cortex responsible for the proliferation of granule cells (GCs) and the establishment of “crude” projection maps with extracerebellar afferent fibers. Finally, the biochemical heterogeneity of PCs allows for a cortical subdivision into distinct functional bands, a presumptive protomap for the development of circuit topography (see in [1]). In this context, the problem of synapse elimination in the process of refinement and stabilization of climbing fiber (CF) connections is also summarized.

1  Department of Neuroscience Rita Levi Montalcini, University of Turin, via Cherasco 15, 10026 Turin, Italy.
2  Neuroscience Institute Cavalieri-Ottolenghi, University of Turin, Regione Gonzole 10, 10043 Orbassano, Turin, Italy.
3  Departments of Pathology & Immunology and Neuroscience, Baylor College of Medicine, Jan and Dan Duncan Neurological Research Institute of Texas Children's Hospital, 1250 Moursund Street, Suite 1325, Houston, Texas 77030, USA.
4  Medical Research Council Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3PT, UK.
5  Department of Cell and Developmental Biology, Vanderbilt University Medical Center, 4114 MRB III, Nashville, TN 37232, USA.
6  Dept. of Microbiology and Physiological Systems and Program in Neuroscience, University of Massachusetts Medical School, 368 Plantation Street, Worcester, MA 01605-2324.
7  Seattle Children's Research Institute, Center for Integrative Brain Research, Seattle, Washington.
8  Department of Pediatrics, Genetics Division, University of Washington, Seattle, Washington.
9  UPMC Université de Paris 06, UMR 7102, 75005 Paris, France.
10  CNRS, UMR 7102, 75005 Paris, France.
11  Laboratory of Developmental Neurobiology, The Rockefeller University, New York, NY USA 10065.
12  Department of Biochemistry and Cellular Biology, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawa-Higashi, Kodaira, Tokyo 187-8502, Japan.
13  Developmental Biology Program, Sloan Kettering Institute, New York, New York 10065.
14  Department of Neurophysiology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.
15  Department of Integrative Physiology, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi, Maebashi, Gunma 371-8511, Japan.
16  Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, 4 Newark Street, London E1 2AT, UK.
17  Dept. Human Anatomy. IMIB-Arrixaca. Univ. Murcia.
18  Department of Anatomy and Cell Biology, Nagoya University Graduate School of Medicine, Japan.
19  Anatomie und Zellbiologie, Anatomisches Institut, Rheinische Friedrich-Wilhelms-Universität, Bonn, Germany.
20  Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611.
21  Institut de la Vision, UPMC Université de Paris 06, Paris 75012, France.
22  Center for Neuropathology, Ludwig-Maximilians-University Munich, Germany.
23  MRC Centre for Developmental Neurobiology, King's College London, UK.
24  Department of Cell Biology & Anatomy and Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, T2N 4NI, Canada. 

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