Elsevier

Neural Networks

Volume 21, Issue 8, October 2008, Pages 1056-1069
Neural Networks

2008 Special Issue
Cerebellar development transcriptome database (CDT-DB): Profiling of spatio-temporal gene expression during the postnatal development of mouse cerebellum

https://doi.org/10.1016/j.neunet.2008.05.004Get rights and content

Abstract

A large amount of genetic information is devoted to brain development and functioning. The neural circuit of the mouse cerebellum develops through a series of cellular and morphological events (including neuronal proliferation and migration, axogenesis, dendritogenesis, synaptogenesis and myelination) all within three weeks of birth. All of these events are controlled by specific gene groups, whose temporal and spatial expression profiles must be encoded in the genome. To understand the genetic basis underlying cerebellar circuit development, we analyzed gene expression (transcriptome) during the developmental stages on a genome-wide basis. Spatio-temporal gene expression data were collected using in situ hybridization for spatial (cellular and regional) resolution and fluorescence differential display, GeneChip, microarray and RT-PCR for temporal (developmental time series) resolution, and were annotated using Gene Ontology (controlled terminology for genes and gene products) and anatomical context (cerebellar cell types and circuit structures). The annotated experimental data were integrated into a knowledge resource database, the Cerebellar Development Transcriptome Database (CDT-DB http://www.cdtdb.brain.riken.jp), with seamless links to the relevant information at various bioinformatics database websites. The CDT-DB not only provides a unique informatics tool for mining both spatial and temporal pattern information on gene expression in developing mouse brains, but also opens up opportunities to elucidate the transcriptome for cerebellar development.

Introduction

The brain is the ultimate genetic system to which a large number of genes are devoted (Sutcliffe, 1988). Data collection at the whole genome level is crucial for comprehensive understanding of the molecular mechanisms underpinning higher-order brain structures and functions of normal brain as well as those of brain diseases in the post-genomic sequencing era (Geschwind, 2000, Hatten and Heintz, 2005). The application of state-of-the-art technologies, including DNA microarrays, on a genome-wide basis, to various aspects of neuroscience, has led to the accumulation of huge amounts of gene expression data; for example, in developing brains (Diaz et al., 2002, Jensen et al., 2004, Kagami and Furuichi, 2001, Matsuki et al., 2005, Mody et al., 2001, Pollard et al., 2006), in neurons in response to neuronal activities (Newton et al., 2003, Tropea et al., 2006), in neuron types (Lein et al., 2004, Sugino et al., 2006, Toledo-Rodriguez et al., 2004) and in ageing brains (Lee et al., 2000, Lu et al., 2004). Most recently, the advent of the neuroinformatics era has enabled us to systematize such large datasets of brain gene expression information in a database, and to create a platform for sharing and mining data; for example, the in situ hybridization (ISH) brain atlas databases GenePaint (Carson et al., 2005, Visel et al., 2004, Visel et al., 2007), Brain Gene Expression Map (BGEM) (Magdaleno et al., 2006) and the Allen Brain Atlas (ABA) (Lein et al., 2007), a database for transcription factor gene expression termed the Functional Genomic Atlas of the Mouse Brain (Gray et al., 2004) and a database for nuclear receptor gene expression termed MousePat (Gofflot et al., 2007).

We have focused on the neural circuit of the mouse cerebellum, which has a layered structure in which there are five major neuronal cell types (Purkinje cells, granule cells, stellate cells, basket cells, and Golgi cells), two major inputs (mossy fibers and climbing fibers), and a single output (Purkinje cell axons) (Ito, 2006). The mouse cerebellar circuit develops through a series of cellular and morphological events (cell proliferation and migration, dendritogenesis and axogenesis, synaptogenesis, myelination, foliation and fissurization) that all occur within the first three weeks of life, and which appear to be genetically coded because of the presence of many cerebellar mutant mice available (Goldowitz & Hamre, 1998). Although the hereditary plan for cerebellar development remains incompletely understood, all of the transcription events (transcriptome) during this period are known to be more complex than those in other mouse organs (Kaplan, 1982, Kaplan, 1987). To understand the genetic basis of cerebellar development we carried out genome-wide profiling of spatial (cellular and regional) and temporal (developmental time series) gene expression patterns in developing mouse brains and systematized them in a database called the Cerebellar Development Transcriptome Database (CDT-DB) (Sato et al., 2004). The CDT-DB is a useful knowledge resource database to share and mine the annotated experimental data on the cerebellar transcriptome.

Section snippets

Genome-wide analyses of spatio-temporal gene expression

ICR and C57B6/J mice (Nihon SLC, Hamamatsu, Japan) were used according to the RIKEN guidelines for animal research. We analyzed spatio-temporal gene expression patterns during the various developmental stages on a genome-wide basis (Sato et al., 2004). Briefly, to search for genes that are differentially expressed in the mouse cerebellum during eight developmental stages (embryonic day [E]18, postnatal day [P]0, P3, P7, P12. P15, P21 and P56), we employed a fluorescence differential display

Acquisition and systematization of spatial and temporal gene expression profiles in the CDT-DB

To understand the genetic basis of postnatal development of the mouse cerebellum, we investigated the spatial (cellular and regional) and temporal (developmental time series) expression patterns of cerebellar development (CD) genes during the developmental stages using genome-wide approaches. Spatio-temporal gene expression profile data were systematized into the Cerebellar Development Transcriptome Database (CDT-DB).

The CDT-DB contains three datasets for temporal gene expression patterns

Discussion

In the present study, we collected and systematized large experimental datasets including information on spatio-temporal gene expression during mouse cerebellar development. The CDT-DB indicates that the postnatal development of the mouse cerebellum is programmed by thousands of different genes, which exhibit differential expression patterns in time and space in developing mouse brains. In addition, we correlated CD gene expression information with relevant biological information by making

Acknowledgements

We thank Ms. Kazuko Yasutake and Ms. Hiroko Kojima for their technical support. We also thank Dr. Jan G. Bjaalie (International Neuroinformatics Coordinating Facility) and Dr. Shiro Usui (Neuroinformatics Japan Center, NIJC) for giving us the opportunity to write this paper. This study was supported by the Institute of Physical and Chemical Research (RIKEN) and NIJC, and by Grants-in-Aid for Scientific Research from the Japanese Ministry of Education, Culture, Sports, Science and Technology

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