Transcriptional Control of Cortical Connectivity
Authors: Anirvan Ghosh
Journal: Neuron (1999)

The development of connections in many regions of the mammalian brain is characterized by the formation of widespread axon projections, followed by elimination of inappropriate axon terminals. For example, layer 5 neurons in the visual cortex initially extend axons into the pons, superior and inferior colliculus, and spinal cord. Later in development, the axonal branches that project to the inferior colliculus and spinal cord are eliminated, leaving behind the mature projection pattern (5Stanfield B.B. O'Leary D.D.M. Fricks C Nature. 1982; 298: 371-373Crossref PubMed Scopus (362) Google Scholar, 4Stanfield B.B. O'Leary D.D.M J. Comp. Neurol. 1985; 238: 236-248Crossref PubMed Scopus (168) Google Scholar). While such large-scale remodeling of axon terminal fields is important for the establishment of functional connections, the molecular mechanisms that regulate this process are not well understood. In this issue of Neuron, 6Weimann J.M. Zhang Y.A. Levin M.E. Devine W.P. Brulet P. McConnell S.K Neuron. 1999; 24 (this issue,): 819-831Abstract Full Text Full Text PDF PubMed Scopus (167) Google Scholar provide evidence that the transcription factor Otx1 is required for the elimination of inappropriate subcortical axon projections. Otx1 is a mammalian homolog of the Drosophila gene orthodenticle, a homeodomain transcription factor (3Simeone A. Acampora D. Gulisano M. Stornaiuolo A. Boncinelli E Nature. 1992; 358: 687-690Crossref PubMed Scopus (665) Google Scholar). Otx1 is expressed in progenitor cells in the cortical ventricular zone and in deep layers of the cortex (2Frantz G.D. Weinmann J.M. Levin M.E. McConnell S.K J. Neurosci. 1994; 14: 5725-5740Crossref PubMed Google Scholar). To determine the function of Otx1 in cortical development, Weimann et al. first examined the pattern of Otx1 protein localization in the developing cerebral wall. They found that Otx1 was excluded from the nucleus in ventricular zone cells, but was predominantly nuclear in a subset of cortical layer 5 neurons, suggesting that there is a regulated translocation of Otx1 into the nucleus during development. By combining retrograde labeling from target structures with Otx1 immunofluorescence, they also found that the Otx1 protein is present in subcortical, but not callosal, projection neurons. To determine the functional significance of Otx1 expression in cortical neurons, Weimann et al. analyzed the consequences of a targeted disruption of Otx1 on the development of cortical efferent projections. The Otx1 mutant mice were generated by targeting the first and second exons of the Otx1 gene (which include most of the homeodomain) (1Acampora D. Mazan S. Avantaggiato V. Barone P. Tuorto F. Lallemand Y. Brulet P. Simeone A Nat. Genet. 1996; 14: 218-222Crossref PubMed Scopus (228) Google Scholar). These mice express a truncated Otx1 protein. While it is difficult to know whether the truncated protein retains any Otx1 function, the protein is likely to be functionally compromised since the homeodomain is disrupted, and Otx1 immunoreactivity is lost (6Weimann J.M. Zhang Y.A. Levin M.E. Devine W.P. Brulet P. McConnell S.K Neuron. 1999; 24 (this issue,): 819-831Abstract Full Text Full Text PDF PubMed Scopus (167) Google Scholar). Somewhat surprisingly, in situ hybridizations using probes to the third exon revealed that transcripts containing that exon are expressed in all layers of the cortical plate in the mutant mice. This is in contrast to normal mice, in which expression is restricted to the deep cortical layers, and suggests that the targeted region of Otx1 might contain DNA sequences that normally restrict Otx1 expression to deep cortical layers. Analysis of the Otx1 mutant mice revealed striking defects in the patterning of subcortical projections. Efferent projections from the mature visual cortex are normally restricted primarily to the thalamus, superior colliculus, and pons. In Otx1 mutant mice, these projections appear normal, but in addition there is extensive innervation of the inferior colliculus and the spinal cord. Since innervation of the inferior colliculus and spinal cord from visual cortex is normally seen early in development but later is eliminated, the phenotype of the Otx1 mutant mice suggests that Otx1 is required for the elimination of exuberant axon projections from inappropriate targets. It is not clear why visual cortical projections to the inferior colliculus and spinal cord are maintained in Otx1 mutant mice. One possibility is that Otx1 function is required for the specification of regional identity in the cortex. Presumptive visual cortical neurons in Otx1 mutant mice might retain their projections to inferior colliculus or spinal cord if their identities were switched to those of auditory or motor cortex. Regional identity, however, appears to be unaffected in the Otx1 mutants as projections from visual cortex to the lateral geniculate nucleus develop normally in these mice (6Weimann J.M. Zhang Y.A. Levin M.E. Devine W.P. Brulet P. McConnell S.K Neuron. 1999; 24 (this issue,): 819-831Abstract Full Text Full Text PDF PubMed Scopus (167) Google Scholar). It would be useful to know if other aspects of regional identity (such as innervation from specific thalamic nuclei) are also normal in Otx1 mutants. An alternate possibility is that Otx1 regulates the responsiveness of cortical projection neurons to signals that control the elimination of inappropriate axon terminals. For instance, elimination of visual cortical axons from the spinal cord might involve expression of a receptor to a repulsive axon guidance cue, or loss of a receptor to a trophic factor. Positive or negative regulation of these receptors by Otx1 could allow the transcription factor to exert an important regulatory influence on the refinement of axonal projections. While this is an attractive model, it should be noted that Otx1 expression cannot be the sole determinant of whether certain subcortical projections are eliminated. In addition to visual cortex, Otx1 is expressed in other cortical areas, such as motor cortex, that maintain projections to the spinal cord. Elimination of exuberant axon projections by visual cortical neurons must therefore involve additional mechanisms. Understanding the mechanisms by which Otx1 regulates region-specific pruning of subcortical projections should provide valuable insight into the problem of cortical connectivity.