Document Detail


Gbx2 regulates thalamocortical axon guidance by modifying the LIM and Robo codes.
MedLine Citation:
PMID:  23136391     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Combinatorial expression of transcription factors forms transcriptional codes to confer neuronal identities and connectivity. However, how these intrinsic factors orchestrate the spatiotemporal expression of guidance molecules to dictate the responsiveness of axons to guidance cues is less understood. Thalamocortical axons (TCAs) represent the major input to the neocortex and modulate cognitive functions, consciousness and alertness. TCAs travel a long distance and make multiple target choices en route to the cortex. The homeodomain transcription factor Gbx2 is essential for TCA development, as loss of Gbx2 abolishes TCAs in mice. Using a novel TCA-specific reporter, we have discovered that thalamic axons are mostly misrouted to the ventral midbrain and dorsal midline of the diencephalon in Gbx2-deficient mice. Furthermore, conditionally deleting Gbx2 at different embryonic stages has revealed a sustained role of Gbx2 in regulating TCA navigation and targeting. Using explant culture and mosaic analyses, we demonstrate that Gbx2 controls the intrinsic responsiveness of TCAs to guidance cues. The guidance defects of Gbx2-deficient TCAs are associated with abnormal expression of guidance receptors Robo1 and Robo2. Finally, we demonstrate that Gbx2 controls Robo expression by regulating LIM-domain transcription factors through three different mechanisms: Gbx2 and Lhx2 compete for binding to the Lmo3 promoter and exert opposing effects on its transcription; repressing Lmo3 by Gbx2 is essential for Lhx2 activity to induce Robo2; and Gbx2 represses Lhx9 transcription, which in turn induces Robo1. Our findings illustrate the transcriptional control of differential expression of Robo1 and Robo2, which may play an important role in establishing the topography of TCAs.
Authors:
Mallika Chatterjee; Kairong Li; Li Chen; Xu Maisano; Qiuxia Guo; Lin Gan; James Y H Li
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2012-11-07
Journal Detail:
Title:  Development (Cambridge, England)     Volume:  139     ISSN:  1477-9129     ISO Abbreviation:  Development     Publication Date:  2012 Dec 
Date Detail:
Created Date:  2012-11-22     Completed Date:  2013-01-31     Revised Date:  2013-12-18    
Medline Journal Info:
Nlm Unique ID:  8701744     Medline TA:  Development     Country:  England    
Other Details:
Languages:  eng     Pagination:  4633-43     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Axons / metabolism,  physiology*
Cells, Cultured
Cerebral Cortex / embryology,  metabolism,  physiology
Embryo, Mammalian
Female
Gene Expression Regulation, Developmental
Homeodomain Proteins / genetics,  metabolism,  physiology*
LIM-Homeodomain Proteins / genetics*,  metabolism
Mice
Mice, Transgenic
Nerve Tissue Proteins / genetics*,  metabolism
Neurogenesis / genetics,  physiology
Pregnancy
Receptors, Immunologic / genetics,  metabolism
Thalamus / embryology*,  metabolism,  physiology
Transcription Factors / genetics,  metabolism
Grant Support
ID/Acronym/Agency:
R01 MH094914/MH/NIMH NIH HHS; R01MH094914/MH/NIMH NIH HHS
Chemical
Reg. No./Substance:
0/Gbx2 protein, mouse; 0/Homeodomain Proteins; 0/LIM-Homeodomain Proteins; 0/Nerve Tissue Proteins; 0/Receptors, Immunologic; 0/Robo2 protein, mouse; 0/Transcription Factors; 0/roundabout protein
Comments/Corrections

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