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The POU proteins Brn-2 and Oct-6 share important functions in Schwann cell development.

ABSTRACT: The genetic hierarchy that controls myelination of peripheral nerves by Schwann cells includes the POU domain Oct-6/Scip/Tst-1and the zinc-finger Krox-20/Egr2 transcription factors. These pivotal transcription factors act to control the onset of myelination during development and tissue regeneration in adults following damage. In this report we demonstrate the involvement of a third transcription factor, the POU domain factor Brn-2. We show that Schwann cells express Brn-2 in a developmental profile similar to that of Oct-6 and that Brn-2 gene activation does not depend on Oct-6. Overexpression of Brn-2 in Oct-6-deficient Schwann cells, under control of the Oct-6 Schwann cell enhancer (SCE), results in partial rescue of the developmental delay phenotype, whereas compound disruption of both Brn-2 and Oct-6 results in a much more severe phenotype. Together these data strongly indicate that Brn-2 function largely overlaps with that of Oct-6 in driving the transition from promyelinating to myelinating Schwann cells.

SUBMITTER: Jaegle M

PROVIDER: S-EPMC196070 | biostudies-literature | 2003 Jun

REPOSITORIES: biostudies-literature

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The POU proteins Brn-2 and Oct-6 share important functions in Schwann cell development.

Jaegle Martine M Ghazvini Mehrnaz M Mandemakers Wim W Piirsoo Marko M Driegen Siska S Levavasseur Francoise F Raghoenath Smiriti S Grosveld Frank F Meijer Dies D

Genes & development 20030601 11

The genetic hierarchy that controls myelination of peripheral nerves by Schwann cells includes the POU domain Oct-6/Scip/Tst-1and the zinc-finger Krox-20/Egr2 transcription factors. These pivotal transcription factors act to control the onset of myelination during development and tissue regeneration in adults following damage. In this report we demonstrate the involvement of a third transcription factor, the POU domain factor Brn-2. We show that Schwann cells express Brn-2 in a developmental pro ...[more]

PMID: 12782656

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Project description:BackgroundA number of cellular processes have evolved in metazoans that increase the proteome repertoire in relation to the genome, such as alternative splicing and translation recoding. Another such process, translational stop codon readthrough (SCR), generates C-terminally extended protein isoforms in many eukaryotes, including yeast, plants, insects, and humans. While comparative genome analyses have predicted the existence of programmed SCR in many species including humans, experimental proof of its functional consequences are scarce.ResultsWe show that SCR of the Drosophila POU/Oct transcription factor Ventral veins lacking/Drifter (Vvl/Dfr) mRNA is prevalent in certain tissues in vivo, reaching a rate of 50% in the larval prothoracic gland. Phylogenetically, the C-terminal extension is conserved and harbors intrinsically disordered regions and amino acid stretches implied in transcriptional activation. Elimination of Vvl/Dfr translational readthrough by CRISPR/Cas9 mutagenesis changed the expression of a large number of downstream genes involved in processes such as chromatin regulation, neurogenesis, development, and immune response. As a proof-of-principle, we demonstrate that the C-terminal extension of Vvl/Dfr is necessary for correct timing of pupariation, by increasing the capacity to regulate its target genes. The extended Vvl/Dfr isoform acts in synergy with the transcription factor Molting defective (Mld) to increase the expression and biosynthesis of the steroid hormone ecdysone, thereby advancing pupariation. Consequently, late-stage larval development was prolonged and metamorphosis delayed in vvl/dfr readthrough mutants.ConclusionsWe demonstrate that translational recoding of a POU/Oct transcription factor takes place in a highly tissue-specific and temporally controlled manner. This dynamic and regulated recoding is necessary for normal expression of a large number of genes involved in many cellular and developmental processes. Loss of Vvl/Dfr translational readthrough negatively affects steroid hormone biosynthesis and delays larval development and progression into metamorphosis. Thus, this study demonstrates how SCR of a transcription factor can act as a developmental switch in a spatiotemporal manner, feeding into the timing of developmental transitions between different life-cycle stages.

Project description:The octamer motif is a common cis-acting regulatory element that functions in the transcriptional control regions of diverse genes and in viral origins of replication. The ability of a consensus octamer motif to stimulate transcription of a histone H2B promoter in frog oocytes suggests that oocytes contain a transcriptionally active octamer-binding protein(s). We show here that frog oocytes and developing embryos contain multiple octamer-binding proteins that are expressed in a sequential manner during early development. Sequences encoding three novel octamer binding-proteins were isolated from Xenopus cDNA libraries by virtue of their homology with the DNA binding (POU) domain of Oct-1. The predicted POU domains of these proteins were most highly related to mammalian Oct-3 (also termed Oct-4), a germ line-specific gene required for mouse early development. Transcripts from these amphibian POU-domain genes were most abundant during early embryogenesis and absent from most adult somatic tissues. One of the genes, termed Oct-60, was primarily expressed as a maternal transcript localized in the animal hemisphere in mature oocytes. The protein encoded by this gene was present in oocytes and early embryos until the gastrula stage of development. Transcripts from a second POU-domain gene, Oct-25, were present at low levels in oocytes and early embryos and were dramatically upregulated during early gastrulation. In contrast to the Oct-60 mRNA, translation of Oct-25 mRNA appeared to be developmentally regulated, since the corresponding protein was detected in embryos during gastrulation but not in oocytes or rapidly cleaving embryos. Transcripts from the third POU protein gene, Oct-91, were induced after the midblastula transition and reached their highest levels of accumulation during late gastrulation. The expression of all three genes decreased during late gastrulation and early neurulation. By analogy with other members of the POU-domain gene family, the products of these genes may play critical roles in the determination of cell fate and the regulation of cell proliferation.

Dataset Information

The POU proteins Brn-2 and Oct-6 share important functions in Schwann cell development.

Publications

The POU proteins Brn-2 and Oct-6 share important functions in Schwann cell development.

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