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Suppression of interneuron programs and maintenance of selected spinal motor neuron fates by the transcription factor AML1/Runx1.

ABSTRACT: Individual spinal motor neuron identities are specified in large part by the intrinsic repertoire of transcription factors expressed by undifferentiated progenitors and maturing neurons. It is shown here that the transcription factor AML1/Runx1 (Runx1) is expressed in selected spinal motor neuron subtypes after the onset of differentiation and is both necessary and sufficient to suppress interneuron-specific developmental programs and promote maintenance of motor neuron characteristics. These findings show an important role for Runx1 during the consolidation of selected spinal motor neuron identities. Moreover, they suggest a requirement for a persistent suppression of interneuron genes within maturing motor neurons.

SUBMITTER: Stifani N

PROVIDER: S-EPMC2359807 | biostudies-other | 2008 Apr

REPOSITORIES: biostudies-other

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Suppression of interneuron programs and maintenance of selected spinal motor neuron fates by the transcription factor AML1/Runx1.

Stifani Nicolas N Freitas Adriana R O AR Liakhovitskaia Anna A Medvinsky Alexander A Kania Artur A Stifani Stefano S

Proceedings of the National Academy of Sciences of the United States of America 20080421 17

Individual spinal motor neuron identities are specified in large part by the intrinsic repertoire of transcription factors expressed by undifferentiated progenitors and maturing neurons. It is shown here that the transcription factor AML1/Runx1 (Runx1) is expressed in selected spinal motor neuron subtypes after the onset of differentiation and is both necessary and sufficient to suppress interneuron-specific developmental programs and promote maintenance of motor neuron characteristics. These fi ...[more]

PMID: 18427115

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

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

Project description: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 LIMcomplex-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 upregulating 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. 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 networks. Our results also demonstrate a general strategy of utilizing embryonic transcription complexes for producing specific cell types from stem cells. Examine the RNA expression profiles of inducible motor neurons-embryonic stem cells (iMN-ESCs) with or without Dox treatment, with biological duplicates.

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