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Strategies for the Generation of Neuronal Diversity in the Developing Central Nervous System

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Strategies for the Generation of Neuronal Diversity in the Developing Central Nervous System The Journal of Neuroscience, November 1995, 75(11): 6987-6998 Feature Article Strategies for the Generation of Neuronal Diversity in the Developing Central Nervous System Susan K. McConnell Department of Biological Sciences, Stanford University, Stanford, California 94305 During development, the neural tube produces a large di- ancestor-in other words, the determination of cell fate by cell versity of neuronal phenotypes from a morphologically ho- lineage. One can imagine two variations on this theme. Under mogeneous pool of precursor cells. In recent years, the the first, a distinct progenitor cell produces a distinct class of cellular and molecular mechanisms by which specific neurons.In this case,clones of related cells would be composed types of neurons are generated have been explored, in the exclusively of neurons with a common phenotype. Under the hope of discovering features common to development second variation on the lineage theme, each precursor might throughout the nervous system. This article focuses on generateneurons with a wide variety of phenotypes, but would three strategies employed by the CNS to generate distinct do so following an intrinsic plan in which different cell types classes of neuronal phenotypes during development: dor- are generated in a predeterminedpattern. In this scheme, the sal-ventral polarization in the spinal cord, segmentation in precursor is multifated (in the sensethat it produces progeny the hindbrain, and a lamination in the cerebral cortex. The that adopt a variety of fates), but lineage studies would reveal mechanisms for neurogenesis exemplified by these three consistentpatterns of clonal compositionfrom animal to animal. strategies range from a relatively rigid, cell lineage-depen- Under the second mechanismthat contributes to the determi- dent specification with a high degree of subservance to nation of specific neuronal fates, neuronal precursors or their early patterns of gene expression, to inductions and cell- progeny are multipotent-that is, the cells may develop along a cell interactions that determine cell fates more flexibly. variety of possiblepathways, and the particular pathway chosen [Key words: neurogenesis, hindbrain, spinal cord, cere- results from interactions between cells and their local microen- bral cortex, pattern formation, homeodomain, induction] vironment. The environment is thought to provide instructive influences that actively signal or induce the production of spe- During embryonic development,the cells of the neural tube gen- cific neuronal phenotypes. erate the enormous variety of neurons that will populate the It is important to emphasizethat lineage studiesalone cannot central nervous system of the adult. Phenotypically diverse neu- reveal the mechanismby which a cell acquires its phenotype. rons must be produced, organized into functional units, and in- Both variable and invariant lineagesmay result from extrinsic terconnectedthrough the formation of specific axonal and syn- inductive events acting on multipotent cells. This apparent par- aptic contacts. These processesultimately generate precisely adox is illustrated by studies of the nematode worm Cuenor- wired neuronal circuits that underlie both simple and complex habditis elegans,in which patterns of cell lineage are completely behaviors. Rather than employing a single, uniform strategy for invariant from animal to animal (Sulston and Horvitz, 1977). the production of neuronal diversity, the neural tube appearsto This invariance led many to the premature conclusion that lin- use a variety of cellular and molecular strategies to generate eage-basedinheritance provides the mechanismfor cell fate de- specific neuronal phenotypes. This article focuseson three such termination. Cell ablation experiments, however, provided ini- strategieswithin the mammaliancentral nervous system: dorsal- tially startling evidence that cell&cell interactions play a crucial ventral patterning in the spinal cord, segmentationin the hind- role in the determinationof many phenotypes-indeed, for many brain, and lamination in the cerebral cortex. These strategies cells it seemsthat the role of lineage is to put the cell in the differ from one another in the cellular mechanismsused to right place at the right time for these interactions to occur achieve diversity, the degree to which cell fates are constrained (Greenwald, 1989). Thus, to ascertain whether intrinsic or ex- by lineage or position, and the extent to which the molecular trinsic influencesdetermine a cell’s fate, one must challengethe basisfor determination is known. cell experimentally to change its normal fate by ablating its There are two general mechanismsthat contribute to the de- neighbors,by transplanting the cell into a foreign environment, termination of specific neuronal fates. One is the inheritance by or by mutating the animal’s genotype (Stent, 1985). a cell of a restricted developmentalpotential from its parent or The Spinal Cord The spinal cord is a tube of cells composedof a relatively small I thank Amy Bohner for comments on the manuscript and Marianne Bronner- Fraser, Tom Jessell, and Chris Walsh for sharing results of experiments prior number of neuronal phenotypes, with relatively minor regional to publication. Supported by NIH EY08411, NIH MH51864, an NSF Presi- heterogeneitiesalong its anterior-posterior axis. The major axis dential Faculty Fellow Award, and a McKnight Scholar Award. Correspondence should be addressed to Dr. Susan K. McConnell at the above of polarization is from dorsal to ventral, with motor neurons address. located ventrally and sensory neuronsfound dorsally in bilateral Copyright 0 1995 Society for Neuroscience 0270.6474/95/156987-12$05.00/O symmetry all along the length of the cord (Fig. 1). Spectacular 6988 McConnell * The Generation of Neuronal Diversity 1993). The presencein the dorsal spinal cord of presumably secretedfactors such as dorsalin-1, a member of the TGFB fam- ily that promotesdorsal development and suppressesmotor neu- ron differentiation (Basler et al., 1993), provides support for this view. In the absenceof the notochord, dorsalin-l expression extends ventrally, consistent with the appearanceof dorsal cell types in ventral locations, and suggestingthat the notochord nor- mally repressesdorsalin-l expression in ventral regions. How- ever, implantation of a secondnotochord above the dorsal neural plate or tube fails to suppressthe formation of dorsal structures such as the neural crest and commissuralinterneurons, which can emerge despite the production of ectopic ventral structures (Artinger and Bronner-Fraser, 1993b). Becausedorsally grafted notochords do appear to repress the dorsal expression of both dorsalin-l (Basler et al., 1993) and wnt-1 (M. Dickinson and M. Bronner-Fraser,unpublished observations), the persistentdiffer- entiation of the neural crest and commissuralinterneurons may have been stimulated by an earlier dorsalizing activity that is unaffected or insufficiently repressedby the ectopic notochord. Motor neuron induction The production of motor neurons in vivo requires a signal de- rived from a ventral source, since removal of the notochord Figure 1. Dorsal-ventral patterning in the embryonic spinal cord. blocks the formation of not only the floor plate but also motor Commissural interneurons are located dorsally and project their axons neurons (Dodd, 1992; Yamada et al., 1993; but seeArtinger and ventrally (their complete axonal trajectories are not shown). Motor neu- rons are located ventrally on either side of the floor plate (FP) and Bronner-Fraser,1993a). These interactions can be reproduced in extend axons into the ventral roots. Abbreviations: E, ectoderm; RP, vitro: juxtaposition of a piece of notochord with an explant of roof plate; N, notochord. lateral neural plate tissue, which would not on its own produce ventral cell types, inducesthe neural explant to form both floor- plate and motor neurons,as assessedby the expressionof mark- progress has been made at both the cellular and molecular levels ers specific to these ventral regions (Placzek et al., 1993; Ya- in understandingthe mechanismsby which dorso-ventral polar- mada et al., 1993). While floorplate induction requires direct ity is initially establishedin the spinal cord. It is by now well contact between notochord and neural tissue in vitro, the signal known that the chordomesodermunderlying the ventral spinal that induces the production of motor neurons appearsto be dif- cord plays an essentialrole in the induction of ventral structures, fusible (Placzek et al., 1993; Yamada et al., 1993). These ob- including the floor plate and neighboring motor neurons. Extir- servations have led to the suggestion that, in contrast to the pation of the notochord results in a failure of both floor plate notion that ventralization results from a single signal, the activ- and motor neurons to differentiate, while grafting an ectopic ities that regulate the production of the floor plate and motor notochord. induces the formation of an ectopic floor plate and neurons are distinct from one another. Both the notochord and accompanying set of motor neurons (reviewed by Dodd, 1992). the floor plate expressclosely-related homologsof the hedgehog Dorsal cell types do not require signals from the notochord gene of Drosophila, called sonic hedgehog(shh) in chick (Eche- for their differentiation; indeed, in the absenceof a notochord, lard et al., 1993) and vertebrate hedgehog(vhh-1) in rat (Roelink dorsal cell types appear ectopically
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