Abstract
Motor neuron (MN) progenitor cells rapidly induce high expression of the transcription factors Islet-1 (Isl1), LIM-homeobox 3 (Lhx3), and the transcriptional regulator LMO4, as they differentiate. While these factors are critical for MN specification, the mechanisms regulating their precise temporal and spatial expression patterns are not well characterized. Isl1 and Lhx3 form the Isl1-Lhx3 complex, which induces the transcription of genes critical for MN specification and maturation. Here, we report that Isl1, Lhx3, and Lmo4 are direct target genes of the Isl1-Lhx3 complex. Our results show that specific genomic loci associated with these genes recruit the Isl1-Lhx3 complex to activate the transcription of Isl1, Lhx3, and Lmo4 in embryonic MNs of chick and mouse. These findings support a model in which the Isl1-Lhx3 complex amplifies its own expression through a potent autoregulatory feedback loop and simultaneously enhances the transcription of Lmo4. LMO4 blocks the formation of the V2 interneuron-specifying Lhx3 complex. In developing MNs, this action inhibits the expression of V2 interneuron genes and increases the pool of unbound Lhx3 available to incorporate into the Isl1-Lhx3 complex. Identifying the pathways that regulate the expression of these key factors provides important insights into the genetic strategies utilized to promote MN differentiation and maturation.
Footnotes
The authors declare no competing financial interests.
This research was supported by grants from NIH/NINDS (R01 NS054941 to S.-K.L.) and NIH/NIDDK (R01 DK064678 to J.W.L. and R01 DK103661 to S.-K.L. and J.W.L.) American Heart Association (to S.-K.L.), and Basic Science Research Program (NRF-2015R1A2A1A15055611) and Bio & Medical Technology Development Program (NRF-2012M3A9C6050508) and the Global Core Research Center funded by the Korean government (MSIP)(2011-0030001) through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT, and future Planning. M.E. was supported by 1F31NS084636 Predoctoral Ruth L. Kirstein National Research Service Award (NRSA) from NIH/NINDS and by the Portland ARCS Chapter.
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