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Lhx2 specifies regional fate in Emx1 lineage of telencephalic progenitors generating cerebral cortex

Nature Neuroscience volume 12, pages 1381–1389 (2009)Cite this article

Abstract

Cerebral cortex is comprised of regions, including six-layer neocortex and three-layer olfactory cortex, generated by telencephalic progenitors of an Emx1 lineage. The mechanism specifying region-specific subpopulations in this lineage is unknown. We found that the LIM homeodomain transcription factor Lhx2 in mice, expressed in graded levels by progenitors, determines their regional identity and fate decisions to generate neocortex or olfactory cortex. Deletion of Lhx2 with Emx1-cre at embryonic day 10.5 (E10.5) altered the fates of progenitors, causing them to generate three-layer cortex, phenocopying olfactory cortex rather than lateral neocortex. Progenitors did not generate ectopic olfactory cortex following Lhx2 deletion at E11.5. Thus, Lhx2 regulates a regional-fate decision by telencephalic progenitors during a critical period that ends as they differentiate from neuroepithelial cells to neuronogenic radial glia. These findings establish a genetic mechanism for determining regional-fate in the Emx1 lineage of telencephalic progenitors that generate cerebral cortex.

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Figure 1: Generation of the loxP-flanked allele of Lhx2 and conditional deletion using Emx1-cre.
Figure 2: Complementary changes in neocortical and paleocortical domains in cerebral cortex of cKO-E mice following Lhx2 deletion by Emx1-cre.
Figure 3: Altered patterns of regional telencephalic markers demonstrate a re-fating of lateral neocortex into piriform cortex following Lhx2 deletion with Emx1-cre, but not Nestin-cre.
Figure 4: Distinct expression patterns of Ctip2 and Satb2 in Lhx2 cKO-E telencephalon indicate that lateral neocortex is re-fated into piriform cortex.
Figure 5: The ePC in lateral neocortex of Lhx2 cKO-E mice receives input from olfactory bulb similar to piriform cortex in wild-type mice.
Figure 6: The ePC located in the lateral neocortex in Lhx2 cKO-E mice is generated by an Emx1 lineage, whereas wild-type piriform cortex is not evident.
Figure 7: Size and extent of ePC in cKO-E mice and piriform cortex in wild-type and cKO-N mice.
Figure 8: Wild-type piriform cortex is generated and forms at appropriate ventral position in Lhx2 cKO-E mice but is subsequently eliminated.

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Acknowledgements

We thank B. Higgins and H. Gutierrez for technical assistance, Y. Nakagawa for help with screening for Lhx2 genomic DNA, K. Jones for Emx1-cre mice, K.-A. Nave for Nex-cre mice, and P.M. Soriano for ROSA26-LacZ reporter mice. This work was supported by grants from the US National Institutes of Health to D.D.M.O.

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Authors and Affiliations

  1. Molecular Neurobiology Laboratory, The Salk Institute, La Jolla, California, USA

    Shen-Ju Chou, Carlos G Perez-Garcia, Todd T Kroll & Dennis D M O'Leary

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  1. Shen-Ju Chou
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  2. Carlos G Perez-Garcia
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  4. Dennis D M O'Leary
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Contributions

S-J.C. designed and generated the loxP-flanked allele of Lhx2, was a principal contributor to analysis of the Lhx2 conditional knockouts, prepared figures and assisted with the writing of the paper. C.G.P.-G. was a principal contributor to the analysis of the Lhx2 conditional knockouts, prepared figures and assisted with the writing of the paper. T.T.K. contributed to the analysis of the Lhx2 conditional knockouts and help to prepare the figures. D.D.M.O. conceived the study, designed and contributed to the analysis of the Lhx2 conditional knockouts, prepared figures and wrote the paper.

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Correspondence to Dennis D M O'Leary.

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Chou, SJ., Perez-Garcia, C., Kroll, T. et al. Lhx2 specifies regional fate in Emx1 lineage of telencephalic progenitors generating cerebral cortex. Nat Neurosci 12, 1381–1389 (2009). https://doi.org/10.1038/nn.2427

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