Perspectives on developmental neurobiology最新文献

Neurological mutant mice have yielded an early and continuously rich resource for studying the role of genes in the developing cerebellum. Experimentally produced chimeric mice, containing mixtures of genetically normal and mutant cells, provided a means of deducing the primary site of gene action and studying cell interactions in these mutant cerebella. Recently, three mutant genes, reeler, weaver, and staggerer, have been cloned and their gene products identified. These three genes have been examined earlier by the chimera technology. Here, we review the chimera studies in the light of what we now know to be the products of these mutant genes.

Neurotrophins are structurally related molecules which regulate the survival and differentiation of various populations of neurons during development. In the cerebellum, the neurotophins and their Trk receptors are expressed at a relatively high level, suggesting an important function for these factors during development. There is also a tight age-dependent and spatial regulation of the molecules in the various cerebellar neurons. Previous studies have shown that BDNF and NT-3 have distinct biological effects on survival and differentiation of cerebellar granule neurons and Purkinje cells. Aside from acting as survival and differentiation factors, the neurotrophins could also have more subtle effects on neuronal function. It is also becoming increasingly evident, not the least from studies in neurotrophin deficient and in cerebellar mutant mice, that the neurotrophins act in concert with other factors and molecules in controlling neuronal development. We will here review some of the recent developments in the neurotrophin field with regard to cerebellum and also discuss what is known about the signaling event following stimulation of cerebellar neurons with BDNF and NT-3. The characterization of specific maturation stages and of genes which are involved and regulated by neurotrophins in developing cerebellum will help us to understand the processes of neuronal survival and differentiation in general.

Experimental studies in chick and analysis of mouse mutants have provided a framework for studying the early developmental processes involved in specifying the cerebellar anlage. Fate mapping studies in chick have shown that at early stages the cerebellum derives from cells in the mesencephalon and metencephalon (mes-met). Transplantation studies in chick have implicated the mes-met junction (isthmus) as a source of secreted factors that organize development of the entire mes-met, perhaps by stimulating proliferation and specifying positional values across the region. Fgf-8 has been implicated as a major factor involved in the isthmus organizing activity. Gene expression studies indicate that the anterior and posterior expression domains of the homeobox genes Otx-2 and Gbx-2, respectively, are the earliest indication of a division of the brain. Furthermore, the Otx-2/Gbx-2 expression border later resides at the mes-met junction. Genetic studies in mouse have shown that Otx-2 and Gbx-2 are required for normal development of cells on both sides of the border. In addition, mutations affecting the secreted factor Wnt-1, which is expressed anterior to the Otx-2/Gbx-2 expression border and the homeodomain transcription factors, Engrailed-1,2 and Pax-2,5 that have broad overlapping expression domains in the mes-met, result in deletions of mes-met structures. Taken together, these studies suggest that specification of the cerebellar territory requires a hierarchy of complex cellular and genetic interactions that gradually subdivide the brain into smaller regions.

The proneural genes in Drosophila render ectodermal cells competent to adopt a neural fate. Moreover, they also initiate the program of mutual inhibition, which will ultimately lead to their own inactivation. Recent advances that elucidate the regulatory relationships between proneural and neurogenic genes are discussed.

The peripheral nervous system (PNS) of the adult Drosophila melanogaster comprises over one thousand sensory organs (bristles and other types of sensilla) displayed in stereotyped positions of the epidermis. This two-dimensional pattern of sensory organs is generated by the emergence of the sensillum mother cells at specific positions of the imaginal discs, the precursors of the adult epidermis. These positions are largely specified by the interplay of three sets of genes: the proneural genes, their antagonists, and the neurogenic genes. The proneural genes confer upon cells the ability to become neural precursors. Among them, achaete and scute, two genes that encode transcriptional activators of the basic region-helix-loop-helix (bHLH) family, are most important for generating the adult PNS. Their expression is restricted to groups of cells, the proneural clusters, which appear at specific positions of the imaginal discs. Sensory organ precursor cells are born within these clusters. The known proneural antagonists either titrate these proteins by forming inactive complexes (extramacrochaetae) or repress achaete/scute expression at specific sites (i.e., hairy). In both cases, they refine sensory organ positioning by reducing the number of cells competent to become sensory organs. The neurogenic genes mediate cell-cell interactions that prevent most competent cells of a proneural cluster from becoming sensory organ mother cells. Depending on the size and shape of the proneural clusters and on their overlaps with regions of maxima or minima of expression of antagonists, sensory organs are generated either as single elements at unique positions, or as linear arrays containing many elements, or as characteristically shaped, two-dimensional arrangements covering specific regions of the fly's body.

The products of the Enhancer of split complex are required during neurogenesis for neural fate to be limited to a subset of cells within the ectoderm. Deletions which remove the complex lead to neural hypertrophy. The complex encodes seven related basic-helix-loop-helix transcription factors which are expressed in response to Notch activation. They accumulate in the cells surrounding the delaminating neuroblast where they prevent cells from adopting the neural fate, most likely by antagonising either directly or indirectly the actions of the proneural genes encoded by the achaete-scute complex. The individual roles of the seven different Enhancer of split proteins remains unclear, since their functions are at least partially redundant. However, the Enhancer of split complex is required in many other processes where Notch is active; the function of the individual proteins may relate to their roles in other developmental decisions or to their expression in distinct regions.

The mammalian cerebellum is subdivided into an elaborate, reproducible array of parasagittal stripes and transverse zones. Stripes and zones are most clearly revealed by the patterns of expression of numerous genes and by the consequences of several naturally-occurring mutations. Because the stripe and zone boundaries are orthogonal, they subdivide the cerebellum into a patchwork grid. How is this elaborate topography created during cerebellar development? This article reviews the evidence for cerebellar regionalization and considers various mechanisms by which it might arise during embryogenesis.

The Drosophila melanogaster Notch gene encodes a receptor that is part of a cell-cell signaling mechanism that is used throughout the development of the fly to regulate a wide variety of cell fate decisions, including some neuronal decisions. The Caenorhabditis elegans Notch-like genes lin-12 and glp-1 play roles that are similar to that of Notch, and studies of this signaling pathway in both organisms have led to models of how the pathway might function. Recent developments in the study of Notch signaling include the isolation of Notch homologs from a variety of vertebrate species. Here we compare what has been learned from studies of Notch-related genes in vertebrates to what is known about Notch signaling in invertebrates, and we discuss the implications of these data for existing models of Notch pathway signaling.