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A network of genetic repression and derepression specifies projection fates in the developing neocortex.

ABSTRACT: Neurons within each layer in the mammalian cortex have stereotypic projections. Four genes-Fezf2, Ctip2, Tbr1, and Satb2-regulate these projection identities. These genes also interact with each other, and it is unclear how these interactions shape the final projection identity. Here we show, by generating double mutants of Fezf2, Ctip2, and Satb2, that cortical neurons deploy a complex genetic switch that uses mutual repression to produce subcortical or callosal projections. We discovered that Tbr1, EphA4, and Unc5H3 are critical downstream targets of Satb2 in callosal fate specification. This represents a unique role for Tbr1, implicated previously in specifying corticothalamic projections. We further show that Tbr1 expression is dually regulated by Satb2 and Ctip2 in layers 2-5. Finally, we show that Satb2 and Fezf2 regulate two disease-related genes, Auts2 (Autistic Susceptibility Gene2) and Bhlhb5 (mutated in Hereditary Spastic Paraplegia), providing a molecular handle to investigate circuit disorders in neurodevelopmental diseases.

SUBMITTER: Srinivasan K

PROVIDER: S-EPMC3511157 | biostudies-literature | 2012 Nov

REPOSITORIES: biostudies-literature

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A network of genetic repression and derepression specifies projection fates in the developing neocortex.

Srinivasan Karpagam K Leone Dino P DP Bateson Rosalie K RK Dobreva Gergana G Kohwi Yoshinori Y Kohwi-Shigematsu Terumi T Grosschedl Rudolf R McConnell Susan K SK

Proceedings of the National Academy of Sciences of the United States of America 20121109 47

Neurons within each layer in the mammalian cortex have stereotypic projections. Four genes-Fezf2, Ctip2, Tbr1, and Satb2-regulate these projection identities. These genes also interact with each other, and it is unclear how these interactions shape the final projection identity. Here we show, by generating double mutants of Fezf2, Ctip2, and Satb2, that cortical neurons deploy a complex genetic switch that uses mutual repression to produce subcortical or callosal projections. We discovered that ...[more]

PMID: 23144223

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Project description:The zebrafish u-boot (ubo) gene encodes the transcription factor Prdm1, which is essential for the specification of the primary slow twitch muscle fibres that derive from adaxial cells. Here we show that Prdm1 executes this function by acting as a transcriptional repressor. Expression of the slow twitch isoform of the myosin heavy chain in adaxial cells is achieved by Prdm1 mediated repression of the transcriptional repressor Sox6. Using Chromatin immuno precipitation (ChIP) we found that genes encoding fast specific isoforms of sarcomeric proteins are direct targets of Prdm1. These genes are ectopically expressed in the adaxial cells of ubotp39 mutant embryos, suggesting that Prdm1 promotes slow twitch fibre differentiation by acting both as a global repressor of fast fibre specific genes as well as of a repressor of slow specific genes. Keywords: ChIP-chip Genomic array design. Microarrays were designed as described below and manufactured by Agilent Technologies (www.agilent.com). We have previously described the ChIP-chip technique in zebrafish and the design of promoter microarrays which cover a 2kb region around the transcription start sites (TSSs) of 11,512 zebrafish genes based on Zv4 (Wardle et al, 2006. Genome Biology 7:R71). In order to capture additional regulatory information further from the basal promoter region we also designed an expanded set of 60mer probes that cover 9kb upstream and 3kb downstream of the TSS of these genes using the same parameters as for the 2kb microarrays. These probe sequences were re-mapped to Zv6 over the course of the project and the coordinates given are for Zv6. We also incorporated several sets of control probes, both positive and negative. On each array there are 769 negative probes designed against zebrafish gene desert regions and Arabidopsis thaliana genes. In addition we included duplicates of promoter probes for several genes that we anticipated may be bound by factors of interest for this and other studies (tnnt3a, mylz2, myhz2, wnt11, flh, vent, msgn1, myod, fgf8, pcdh8) and these probes are arrayed on both slides slide. Finally on each array there are 1804 controls added by Agilent. The final design contained 352,490 probes divided between two microarray slides. Further information on design and manufacture of the microarrays can be found at the Agilent Technologies website.

Dataset Information

A network of genetic repression and derepression specifies projection fates in the developing neocortex.

Publications

A network of genetic repression and derepression specifies projection fates in the developing neocortex.

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