Fusion protein Isl1-Lhx3 specifies motor neuron fate by inducing motor neuron genes and concomitantly suppressing the interneuron programs.

Proceedings of the National Academy of Sciences of the United States of America
Seunghee LeeSoo-Kyung Lee

Abstract

Combinatorial transcription codes generate the myriad of cell types during development and thus likely provide crucial insights into directed differentiation of stem cells to a specific cell type. The LIM complex composed of Isl1 and Lhx3 directs the specification of spinal motor neurons (MNs) in embryos. Here, we report that Isl1-Lhx3, a LIM-complex mimicking fusion, induces a signature of MN transcriptome and concomitantly suppresses interneuron differentiation programs, thereby serving as a potent and specific inducer of MNs in stem cells. We show that an equimolar ratio of Isl1 and Lhx3 and the LIM domain of Lhx3 are crucial for generating MNs without up-regulating interneuron genes. These led us to design Isl1-Lhx3, which maintains the desirable 1:1 ratio of Isl1 and Lhx3 and the LIM domain of Lhx3. Isl1-Lhx3 drives MN differentiation with high specificity and efficiency in the spinal cord and embryonic stem cells, bypassing the need for sonic hedgehog (Shh). RNA-seq analysis revealed that Isl1-Lhx3 induces the expression of a battery of MN genes that control various functional aspects of MNs, while suppressing key interneuron genes. Our studies uncover a highly efficient method for directed MN generation and MN gene netwo...Continue Reading

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Citations

Jun 27, 2013·Proceedings of the National Academy of Sciences of the United States of America·Seunghee LeeSoo-Kyung Lee
Feb 20, 2014·Stem Cells and Development·Ruchi SharmaFrancesc Xavier Donadeu
Sep 21, 2013·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Mingqian HuangZheng-Yi Chen
Dec 3, 2014·Neuroscience Letters·Shao-jun SongXiao-yan Xue
Feb 25, 2015·Developmental Cell·Heekyung Jung, Jeremy S Dasen
Nov 8, 2016·Scientific Reports·Kyung-Tai KimMi-Ryoung Song
Jul 28, 2015·Nature Communications·Karen P ThiebesSoo-Kyung Lee
Feb 26, 2020·Journal of Biomedical Science·Kuan-Wei Chen, Jun-An Chen
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