TY - JOUR T1 - The Isl1-Lhx3 Complex Promotes Motor Neuron Specification by Activating Transcriptional Pathways that Enhance its Own Expression and Formation JF - eneuro JO - eNeuro DO - 10.1523/ENEURO.0349-16.2017 SP - ENEURO.0349-16.2017 AU - Madalynn Erb AU - Bora Lee AU - So Yeon Seo AU - Jae W. Lee AU - Seunghee Lee AU - Soo-Kyung Lee Y1 - 2017/03/28 UR - http://www.eneuro.org/content/early/2017/03/28/ENEURO.0349-16.2017.abstract N2 - Motor neuron progenitor cells rapidly induce high expression of the transcription factors Isl1, Lhx3, and the transcriptional regulator LMO4, as they differentiate. While these factors are critical for motor neuron 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 motor neuron 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 motor neurons 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 motor neurons, 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 motor neuron differentiation and maturation.Significance Statement The precise temporal and spatial regulation of transcription factor expression is critical for embryos to generate the appropriate number and variety of motor neurons. This process dictates the formation of motor circuits, which regulate coordinated movement and homeostasis. When motor neuron specification is impaired, it leads to serious medical conditions such as spinal muscular atrophy. Understanding motor neuron development is crucial for effectively treating pediatric motor neuron disorders and neurodegenerative disorders, such as amyotrophic lateral sclerosis. Here we show that three essential factors for motor neuron development, Isl1, Lhx3 and LMO4 are induced directly by the Isl1-Lhx3 complex. Characterizing the pathways that direct the expression of these factors provides key insights into the genetic mechanisms that regulate motor neuron development. ER -