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Molecular Control of Central and Peripheral Nervous System Development Stefan Britsch (Helmholtz Fellow) The ability of the mature nervous system to integrate, compute, and distribute information results from developmental processes that create diversity, connectivity, and the spatial organization of neurons. Our group is interested in understanding the molecular mechanisms and regulatory networks, which orchestrate the ordered spatiotemporal appearance of these developmental events. Current research from our group focuses on the systematic identification and functional characterization of genes involved in the molecular control of diversification, circuit formation and spatial organization of neurons in the central nervous system. To address this we combine systematic genomic screens with gain-/loss-of-function studies in vivo and in vitro. By the help of this strategy, we have recently identified several novel candidate genes, and demonstrated that one of these factors, the Krüppel-C 2 H 2 zinc finger transcription factor Bcl11a, has a key role in morphogenesis and circuit formation in neurons of the central nervous system. Genomic and functional analysis of dorsal spinal cord development The dorsal spinal cord is a major processing center that integrates somatosensory information, like touch, pain, temperature and proprioception, and relays it to secondary brain centers. These functions reside in a large number of diverse interneuron populations located in the dorsal spinal cord. Sensory interneurons can modulate, enhance, and even – in the case of central pain control – suppress sensory input. Spinal sensory interneurons have been characterized by their physiological and morphological properties, and by their laminar position in the dorsal horn. However, the molecular mechanisms that control their differentiation and functional integration into complex neuronal circuits are incompletely understood. To identify candidate genes, with putative functions in the development of the dorsal spinal cord, we have performed a differential genomic screen with high-density oligonucleotide microarrays. By comparison of expression profiles of ventral and dorsal spinal cords, we identified genes that are enriched in the dorsal neural tube. Included among the differentially expressed genes are those with known functions in spinal cord development, as well as other genes with as yet unknown functions. Within this group of genes we have identified the homeodomain transcription factor Gbx1 and two Krüppel-C 2 H 2 zinc finger transcription factors, Bcl11a and Bcl11b. Recent work from our group has demonstrated that Gbx1 is expressed specifically in a subset of Lbx1 + (class B) neurons in the dorsal spinal horn. Expression of Gbx1 in the dorsal spinal cord depends on Lbx1 function. Gbx1 identifies a distinct population of late-born, Lhx1/5 + , Pax2 + neurons. In the perinatal period, Gbx1 marks a subpopulation of GABAergic neurons. The expression of Gbx1 suggests that it controls the development of a specific subset of GABAergic neurons in the dorsal horn of the spinal cord. We have generated loss-of-function mutations of the Gbx1 gene in mice for further analysis of its role in the developing spinal cord. Homozygous mutant mice are viable, however, during adolescence these mice develop neurological symptoms indicating defective spinal processing of somatosensory information. Bcl11a and b are closely related C 2 H 2 zinc finger transcription factors, which have previously been shown to be essential for the development of B- und T-lymphocytes, respectively. Furthermore, chromosomal aberrations of Bcl11a and b have been reported from various lymphoid malignancies in humans. Both genes are also expressed in the embryonic brain, spinal cord and peripheral nervous system. There is emerging evidence that common regulatory mechanisms are utilized during embryogenesis to control the development of independent organ systems. This is particularly evident for the development of the lympho-haemopoietic and the nervous system. To analyze functions of Bcl11a and b in nervous system development we have generated CNS-specific conditional mouse mutants for the Bcl11a and b genes (collaboration with Neal Copeland, NCI Frederick). Conditional mutant animals die after birth, indicating that both genes serve critical functions during nervous system development. Our phenotype analysis of the Bcl11a mutants demonstrates that the gene is critical for neuronal morphogenesis, and circuit formation within the dorsal spinal horn. Bcl11a is also expressed in other regions of the brain (i.e. hippocampus, cerebellum). Phenotype analysis of mice with conditional mutations of Bcl11a restricted to these brain areas indicates that Bcl11a has similar functions in hippocampal, and cerebellar neurons as observed for the spinal 156 Function and Dysfunction of the Nervous System
Stucture of the Group Group Leader Prof. Dr. Stefan Britsch Technical Assistant Verena Sasse* Graduate Students Heike Brylka* Anita John* * part of the period reported Lateral view of an E10.5 mouse embryo after whole-mount in situ hybridization with a Prox2 specific riboprobe. Note that Prox2 expression is restricted to the regions where viscerosensory ganglia form. neurons. This suggests a general function of this factor during CNS development. We have begun to analyze functions of the closely related Bcl11b gene during nervous system development. In the developing dorsal spinal cord expression of Bcl11a and b partially overlap. However, our preliminary phenotype analysis indicates that both genes have divergent developmental functions. Functional analysis of the Prospero-related homeodomain transcription factor Prox2 during development of viscerosensory neurons In vertebrates, peripheral sensory neurons derive either from placodal or from neural crest cells. Placodes are focal regions of thickened ectoderm in the vertebrate head, which give rise to both neuronal and non-neuronal cells. Cranial placodes include a series of three epibranchial placodes, which generate viscerosensory neurons. Such neurons relay taste stimuli to the brainstem and participate in neuronal cricuits that are critical for the central control of respiration and heart function. We have shown that the novel murine Prospero-related homeodomain transcription factor Prox2 is exclusively expressed in a subgroup of placode-derived viscerosensory neurons (see figure). Members of the Prosperofamily have been previously demonstrated to control cellfate decisions and neuronal differentiation in the developing nervous system. We have therefore generated mice with a targeted deletion of the Prox2 gene to further analyze the functions of this gene during embryonic development of viscerosensory neurons. Selected Publications Britsch S (2007) The Neuregulin-1/ErbB signalling system in development and disease. Adv Anat Embryol Cell Biol 190:1-65. Britsch S (2006) Transgenic and Knockout Animals. In: Ganten D, Ruckpaul K (eds.) Encyclopedic Reference of Genomics and Proteomics in Molecular Medicine. Springer-Verlag, Heidelberg, New York. John A, Wildner H, Britsch S (2005) The homeodomain transcription factor Gbx1 identifies a subpopulation of late-born GABAergic interneurons in the developing dorsal spinal cord. Dev Dyn 234:767-771. Müller T, Anlag K, Wildner H, Britsch S, Treier M, Birchmeier C (2005) The bHLH factor Olig3 coordinates the specification of dorsal neurons in the spinal cord. Genes Dev 19: 733-743. Function and Dysfunction of the Nervous System 157
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