Cortical Neurons Require Otx1 for the Refinement of Exuberant Axonal Projections to Subcortical Targets

Weimann, James M.; Zhang, Y.Alex; Levin, Margaret; Devine, W. Patrick; Brûlet, Philippe; McConnell, Susan K.

doi:10.1016/s0896-6273(00)81030-2

Cited by 183 publications

(120 citation statements)

References 63 publications

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“…3C); ROR␤ for layer IV ( Fig. 3E; Weimann et al 1999), mSorLA or Svet1 for layers II/III and SVZ cells ( Fig. 3G; data not shown; Hermans-Borgmeyer et al 1998;Tarabykin et al 2001), …”

Section: Resultsmentioning

confidence: 85%

Brn-1 and Brn-2 share crucial roles in the production and positioning of mouse neocortical neurons

Sugitani¹,

Nakai²,

Minowa³

et al. 2002

Genes Dev.

231

244

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Formation of highly organized neocortical structure depends on the production and correct placement of the appropriate number and types of neurons. POU homeodomain proteins Brn-1 and Brn-2 are coexpressed in the developing neocortex, both in the late precursor cells and in the migrating neurons. Here we show that double disruption of both Brn-1 and Brn-2 genes in mice leads to abnormal formation of the neocortex with dramatically reduced production of layer IV-II neurons and defective migration of neurons unable to express mDab1. These data indicate that Brn-1 and Brn-2 share roles in the production and positioning of neocortical neuron development. Received January 22, 2002; revised version accepted May 23, 2002. The mature neocortex is organized into six cell layers, each of which contains neurons with similar morphologies, molecular properties, and projection patterns. The development of this neocortical structure depends on a highly ordered pattern of neuronal production and migration. Cortical neurons that comprise each layer are sequentially produced in the ventricular zone of the dorsal telencephalon (Angevine and Sidman 1961;Takahashi et al. 1999). Although the regulatory factors that function in this sequential production of a variety of layer-specific neurons have not been identified in mammals, in Drosophila the successive production of different types of cells from neuroblasts has been found to require a temporally stereotyped pattern of expression of a set of transcription factors including the Drosophila POU transcription factors Pdm1 and Pdm2 (Isshiki et al. 2001). In mammals, newly produced neurons leave their birthplace, migrate toward the cortical surface, and form cortical layers in an inside-out pattern with respect to their time of birth (Angevine and Sidman 1961;Rakic 1972). Recent genetic studies have identified large numbers of functional molecules involved in the migration/ positioning of neocortical neurons (for review, see Rice and Curran 1999).Brn-1 and Brn-2, members of the mammalian class III POU transcription factor family, are prominently expressed in the embryonic brain, including the neocortex (He et al. 1989). Each single mutant, however, shows abnormalities only in limited brain regions. In Brn-2 mutant neonates, neuronal loss was observed only in the hypothalamic supraoptic and paraventricular nuclei, where Brn-1 is not expressed (Nakai et al. 1995;Schonemann et al. 1995). In Brn-1 mutants, remarkable changes in brain morphology were observed only in the hippocampus, where Brn-2 expression is barely detectable (data not shown). In the neocortex, where both Brn-1 and Brn-2 are expressed, no overt developmental defects were seen in either single mutant. These observations suggest functional complementation between Brn-1 and Brn-2 in neocortical development. Results and DiscussionTo explore their possible overlapping functions in neocortical development, we generated Brn-1/Brn-2 double homozygous mutants by intercrossing double heterozygotes that were healthy and fertile, wi...

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“…3C); ROR␤ for layer IV ( Fig. 3E; Weimann et al 1999), mSorLA or Svet1 for layers II/III and SVZ cells ( Fig. 3G; data not shown; Hermans-Borgmeyer et al 1998;Tarabykin et al 2001), …”

Section: Resultsmentioning

confidence: 85%

Brn-1 and Brn-2 share crucial roles in the production and positioning of mouse neocortical neurons

Sugitani¹,

Nakai²,

Minowa³

et al. 2002

Genes Dev.

231

244

View full text Add to dashboard Cite

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“…60,61 A relation might also be anticipated between synaptic markers and other gene products involved in axon guidance and pruning, such as ephrins, 62 cadherins, 63 and Otx1. 64 Overall, we assume that sema3A is but one component of a complex set of related gene expression alterations occurring in subjects with schizophrenia across the life span, which together ultimately represent the molecular neuropathology of the disorder. The sequencing of the genome and the advent of large-scale expression arrays and proteomics together allow this fundamental issue to begin to be addressed systematically.…”

Section: Discussionmentioning

confidence: 99%

The axonal chemorepellant semaphorin 3A is increased in the cerebellum in schizophrenia and may contribute to its synaptic pathology

et al. 2003

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The neuropathological features of schizophrenia are suggestive of a developmentally induced impairment of synaptic connectivity. Semaphorin 3A (sema3A) might contribute to this process because it is a secreted chemorepellant which regulates axonal guidance. We have investigated sema3A in the cerebellum (an area in which expression persists in adulthood), and measured its abundance in 16 patients with schizophrenia and 16 controls. In adults, sema3A was predominantly localized to the inner part of the molecular layer neuropil, whereas infants and rats showed greater labelling of Purkinje cell bodies. Sema3A was increased in schizophrenia, as shown by enzyme-linked immunosorbent assay ( þ 28%; Po0.05) and immunohistochemistry ( þ 45%; Po0.01). We also measured reelin mRNA, since reelin is involved in related developmental processes and is decreased in other brain regions in schizophrenia. Reelin mRNA showed a trend reduction in the subjects with schizophrenia (À26%; P ¼ 0.07) and, notably, was negatively correlated with sema3A. Sema3A also correlated negatively with synaptophysin and complexin II mRNAs. The results show that sema3A is elevated in schizophrenia, and is associated with downregulation of genes involved in synaptic formation and maintenance. In this respect, sema3A appears to contribute to the synaptic pathology of schizophrenia, perhaps via ongoing effects of persistent sema3A elevation on synaptic plasticity. The findings are consistent with an early neurodevelopmental origin for the disorder, and the reciprocal changes in sema3A and reelin may be indicative of a pathogenic mechanism that affects the balance between trophic and inhibitory factors regulating synaptogenesis.

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“…To explore the fates of layer 5 and 6 neurons in Fezl Ϫ/Ϫ brains, we performed in situ hybridization at embryonic day (E)14 and postnatal day (P)0 and P15 for genes that distinguish these neurons from those in other layers. The expression of some deep-layer genes, such as Otx1 (20) and Tbr1 (11), was unaffected in the Fezl Ϫ/Ϫ cortex ( Fig. 7 A-D), suggesting that Fezl-deficient mice produce layer 5 and 6 neurons [including corticospinal motor neurons (CSMNs), which express Otx1 (20)]; however, the expression of other deep-layer markers was severely disrupted (Table 1).…”

Section: Disruption Of Molecular Markers For Deep Cortical Layers In mentioning

confidence: 99%

“…The expression of some deep-layer genes, such as Otx1 (20) and Tbr1 (11), was unaffected in the Fezl Ϫ/Ϫ cortex ( Fig. 7 A-D), suggesting that Fezl-deficient mice produce layer 5 and 6 neurons [including corticospinal motor neurons (CSMNs), which express Otx1 (20)]; however, the expression of other deep-layer markers was severely disrupted (Table 1). Two mRNAs expressed in layer 5, ER81 and Foxo1, were greatly reduced or completely absent in the Fezl Ϫ/Ϫ cortex ( Fig.…”

Section: Disruption Of Molecular Markers For Deep Cortical Layers In mentioning

confidence: 99%

Fezl regulates the differentiation and axon targeting of layer 5 subcortical projection neurons in cerebral cortex

Chen

Schaevitz

McConnell

2005

Proc. Natl. Acad. Sci. U.S.A.

333

400

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During the development of the cerebral cortex, progenitor cells produce neurons that migrate to laminar positions appropriate for their birth dates, adopt specific neuronal identities, and form appropriate local and long-distance axonal connections. Here, we report that forebrain embryonic zinc-finger-like protein (Fezl), a putative zinc-finger transcriptional repressor, is required for the differentiation of projection neurons in cortical layer 5. In Fezldeficient mice, these neurons display molecular, morphological, and axonal targeting defects. The corticospinal tract was absent in Fezl ؊/؊ mice, corticotectal and pontine projections were severely reduced, and Fezl-expressing neurons formed aberrant axonal projections. The expression of many molecular markers for deeplayer neurons was reduced or absent in the Fezl ؊/؊ cerebral cortex. Most strikingly, Ctip2, a transcription factor required for the formation of the corticospinal tract, was not expressed in the Fezl-deficient cortex. These results suggest that Fezl regulates the differentiation of layer 5 subcortical projection neurons.axon guidance ͉ cell fate ͉ corticospinal tract ͉ zinc-finger transcription factor

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Cortical Neurons Require Otx1 for the Refinement of Exuberant Axonal Projections to Subcortical Targets

Cited by 183 publications

References 63 publications

Brn-1 and Brn-2 share crucial roles in the production and positioning of mouse neocortical neurons

Brn-1 and Brn-2 share crucial roles in the production and positioning of mouse neocortical neurons

The axonal chemorepellant semaphorin 3A is increased in the cerebellum in schizophrenia and may contribute to its synaptic pathology

Fezl regulates the differentiation and axon targeting of layer 5 subcortical projection neurons in cerebral cortex

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