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Hes-1 regulates the excitatory fate of neural progenitors through modulation of Tlx3 (HOX11L2) expression

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Abstract

Tlx3 (HOX11L2) is regarded as one of the selector genes in excitatory versus inhibitory fate specification of neurons in distinct regions of the nervous system. Expression of Tlx3 in a post-mitotic immature neuron favors a glutamatergic over GABAergic fate. The factors that regulate Tlx3 have immense importance in the fate specification of glutamatergic neurons. Here, we have shown that Notch target gene, Hes-1, negatively regulates Tlx3 expression, resulting in decreased generation of glutamatergic neurons. Down-regulation of Hes-1 removed the inhibition on Tlx3 promoter, thus promoting glutamatergic differentiation. Promoter–protein interaction studies with truncated/mutated Hes-1 protein suggested that the co-repressor recruitment mediated through WRPW domain of Hes-1 has contributed to the repressive effect. Our results clearly demonstrate a new and unique role for canonical Notch signaling through Hes-1, in neurotransmitter/subtype fate specification of neurons in addition to its known functional role in proliferation/maintenance of neural progenitors.

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Acknowledgments

This work was supported by research grants from the Department of Science & Technology and the Department of Biotechnology, Government of India, and Intra mural grants from RGCB to JJ; CLI, RS, MSD, VAR and SBD were supported by research fellowships from CSIR & ICMR, Government of India. The authors thank Dr. R Kageyama, Dr. R Kopan, Dr. Anderstrom, Dr. Minato and Addgene for generously providing us the plasmid constructs.

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Authors and Affiliations

  1. Neuro Stem Cell Biology Laboratory, Department of Neurobiology, Rajiv Gandhi Center for Biotechnology, Thycaud PO, Poojappura, Thiruvananthapuram, Kerala, 695 014, India

    Chandrasekharan Lalitha Indulekha, Thulasi Sheela Divya, Mundackal Sivaraman Divya, Rajendran Sanalkumar, Vazhanthodi Abdul Rasheed, Sivadasan Bindu Dhanesh, Anu Sebin, Amitha George & Jackson James

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  1. Chandrasekharan Lalitha Indulekha
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  2. Thulasi Sheela Divya
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  3. Mundackal Sivaraman Divya
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  9. Jackson James
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Correspondence to Jackson James.

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C. L. Indulekha and T. S. Divya contributed equally to this work.

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Indulekha, C.L., Divya, T.S., Divya, M.S. et al. Hes-1 regulates the excitatory fate of neural progenitors through modulation of Tlx3 (HOX11L2) expression. Cell. Mol. Life Sci. 69, 611–627 (2012). https://doi.org/10.1007/s00018-011-0765-8

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