Abstract
The homeodomain transcription factor Prrxl1/DRG11 has emerged as a crucial molecule in the establishment of the pain circuitry, in particular spinal cord targeting of dorsal root ganglia (DRG) axons and differentiation of nociceptive glutamatergic spinal cord neurons. Despite Prrxl1 importance in the establishment of the DRG-spinal nociceptive circuit, the molecular mechanisms that regulate its expression along development remain largely unknown. Here, we show that Prrxl1 transcription is regulated by three alternative promoters (named P1, P2, and P3), which control the expression of three distinct Prrxl1 5'-UTR variants, named 5'-UTR-A, 5'-UTR-B, and 5'-UTR-C. These 5'-UTR sequences confer distinct mRNA stability and translation efficiency to the Prrxl1 transcript. The most conserved promoter (P3) contains a TATA-box and displays in vivo enhancer activity in a pattern that overlaps with the zebrafish Prrxl1 homologue, drgx. Regulatory modules present in this sequence were identified and characterized, including a binding site for Phox2b. Concomitantly, we demonstrate that zebrafish Phox2b is required for the expression of drgx in the facial, glossopharyngeal, and vagal cranial ganglia.
Highlights
The mechanisms that control the Prrxl1 expression are poorly understood
The Prrxl1 mRNA sequence described by these authors contained the start codon in exon 2, whereas exon 1 corresponded to a 5Ј-untranslated regions (5Ј-UTRs)
To shed some light on the molecular mechanisms regulating Prrxl1 gene expression, we isolated and characterized the alternative promoters that control the expression of three distinct Prrxl1 5Ј-UTR variants, named 5Ј-UTR-A, 5Ј-UTR-B, and 5Ј-UTR-C
Summary
Results: Several regulatory elements present in Prrxl alternative promoters are functionally characterized, including a binding motif for Phox2b required for Prrxl expression in visceral sensory neurons. Spinal sensory neurons differentiate from several classes of proliferating progenitor cells, whose establishment requires the expression of proneural genes encoding for basic helixloop-helix (bHLH) transcription factors [3,4,5]. Prrxl expression in various cell lineages in DRG and spinal cord is well known, the mechanisms of transcriptional control exerted by different bHLH and homeodomain proteins that modulate Prrxl transcription are still poorly understood. We characterize three Prrxl1 5Ј-UTRs variants and the corresponding promoter regions, which may explain the differential involvement of Prrxl in the DRG and spinal cord development. We present in vitro and in vivo evidence that the most evolutionarily conserved Prrxl promoter region is sufficient to drive expression to neuronal cells and is regulated by Phox2b in primary afferent neurons
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
