Regulation of Schwann cell differentiation and proliferation by the Pax‐3 transcription factor

Doddrell, Robin D. S.; Dun, Xin‐Peng; Moate, Roy; Jessen, Kristján R.; Mirsky, Rhona; Parkinson, David B.

doi:10.1002/glia.22346

Cited by 54 publications

(51 citation statements)

References 61 publications

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“…studies have shown that Pax3 induces proliferation and inhibits apoptosis of Schwann cells (Doddrell et al, 2012) and also has a principal role in the regulation of dorsolateral melanocyte differentiation (Lang et al, 2005). Downregulation of Pax3 correlates with Oct6 and Krox20 (Egr2; early growth response 2) upregulation (which occurs at E17-P3) in promyelinating Schwann cells (Blanchard et al, 1996) and supports the supposition that Pax3 inhibits the myelination gene program (Kioussi et al, 1995;Doddrell et al, 2012).…”

Section: As In Vitro Primermentioning

confidence: 69%

“…Downregulation of Pax3 correlates with Oct6 and Krox20 (Egr2; early growth response 2) upregulation (which occurs at E17-P3) in promyelinating Schwann cells (Blanchard et al, 1996) and supports the supposition that Pax3 inhibits the myelination gene program (Kioussi et al, 1995;Doddrell et al, 2012). It is certainly intriguing to consider possible Pax3, Sox10, Mitf, Nrg1 (neuregulin 1), Igf1 and Pdgf gene regulatory networks that function in the specification of ISCs versus melanoblasts at this stage.…”

Section: As In Vitro Primermentioning

confidence: 71%

“…Pax3 in regenerative Schwann cells, as in embryogenesis, is thus thought to oppose myelination and withdrawal from the cell cycle (Doddrell et al, 2012).…”

Section: Aberrant Pax Gene Expression: Implications For Regeneration mentioning

confidence: 99%

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Pax genes: regulators of lineage specification and progenitor cell maintenance

2014

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Pax genes encode a family of transcription factors that orchestrate complex processes of lineage determination in the developing embryo. Their key role is to specify and maintain progenitor cells through use of complex molecular mechanisms such as alternate RNA splice forms and gene activation or inhibition in conjunction with protein co-factors. The significance of Pax genes in development is highlighted by abnormalities that arise from the expression of mutant Pax genes. Here, we review the molecular functions of Pax genes during development and detail the regulatory mechanisms by which they specify and maintain progenitor cells across various tissue lineages. We also discuss mechanistic insights into the roles of Pax genes in regeneration and in adult diseases, including cancer. KEY WORDS: Pax genes, Embryogenesis, Lineage determination IntroductionPaired box (Pax) genes encode transcription factors that contain a highly conserved DNA-binding domain called the paired domain (PD, Fig. 1A) and can be considered to be a principle regulator of gene expression. Nine Pax genes (Pax1-Pax9) have been characterised in mammals and the evolutionary conserved paired domain has been identified across phylogenies from insects, to amphibians and birds. In higher vertebrates, PAX proteins are subclassified into groups according to inclusion of an additional DNA-binding homeodomain and/or an octapeptide region, which serves as a binding motif for protein co-factors for potent inhibition of downstream gene transcription (Eberhard et al., 2000) (Fig. 1B); all PAX proteins include a transactivation domain located within the C-terminal amino acids (Underhill, 2012). It is also known that all Pax genes, with the exception of Pax4 and Pax9, produce alternative RNA transcripts (see Table 1). The functional diversity of Pax proteins in vivo is thus linked to the ability to produce alternatively spliced gene products that differ in structure and, consequently, in the binding activity of their paired and homeodomain DNA-binding regions (Underhill, 2012).Three decades ago, the characterisation and roles of Pax genes in embryonic development began to unfold. Early studies discovered that regulatory gene families such as the Pax family are involved in the sequential compartmentalisation and body patterning of developing organisms; thereafter, studies highlighted a role for Pax genes in the early specification of cell fate and the subsequent morphogenesis of various tissues and organs. Following this, mutational studies of Pax genes confirmed the importance of these regulatory roles in the PRIMER School of Medical Sciences, Edith Cowan University, Joondalup, WA 6027, Australia.*Author for correspondence (j.blake@ecu.edu.au) This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.initiation and progression of ...

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Section: As In Vitro Primermentioning

confidence: 69%

Section: As In Vitro Primermentioning

confidence: 71%

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Pax genes: regulators of lineage specification and progenitor cell maintenance

2014

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“…These pathways include Raf/ERK signaling and the transcriptional regulators Notch and c-Jun. Other transcription factors, like Notch and cJun, are characterized as negative regulators of myelination, including Sox2, Pax3, and Id4, are implicated in a similar function (Jessen and Mirsky 2008), as are the JNK and p38 MAP kinase pathways (Kioussi et al 1995;Le et al 2005;Mager et al 2008;Doddrell et al 2012;Hossain et al 2012;Yang et al 2012;DK Wilton, R Mirsky, and KR Jessen, unpubl. ).…”

Section: Control and Maintenance Of The Repair Phenotypementioning

confidence: 99%

Schwann Cells: Development and Role in Nerve Repair

Jessen

Mirsky

Lloyd

2015

Cold Spring Harb Perspect Biol

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607

539

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Schwann cells develop from the neural crest in a well-defined sequence of events. This involves the formation of the Schwann cell precursor and immature Schwann cells, followed by the generation of the myelin and nonmyelin (Remak) cells of mature nerves. This review describes the signals that control the embryonic phase of this process and the organogenesis of peripheral nerves. We also discuss the phenotypic plasticity retained by mature Schwann cells, and explain why this unusual feature is central to the striking regenerative potential of the peripheral nervous system (PNS).T he myelin and nonmyelin (Remak) Schwann cells of adult nerves originate from the neural crest in well-defined developmental steps ( Fig. 1). This review focuses on embryonic development (for additional information on myelination, see Salzer 2015). We also discuss how the ability to change between differentiation states, a characteristic attribute of developing cells, is retained by mature Schwann cells, and explain how the ability of Schwann cells to change phenotype in response to injury allows the peripheral nervous system (PNS) to regenerate after damage. TWO TYPES OF EMBRYONIC NERVESAdult nerves are stable structures in which the nerve fibers are protected structurally by a collagen-rich, vascularized extracellular matrix (the endoneurium) linked to the basal lamina surrounding each axon -Schwann cell unit. The endoneurial environment is further protected by a surrounding multilayered cellular tube (the perineurium) that shields the nerve fibers from unwanted cells and molecules (Fig. 2).A more dynamic and radically different structure, reminiscent of axon -glial organization in the central nervous system (CNS), is seen in early embryonic nerves (embryo day E14/15 in rat hind limb and E12/13 in mouse). These nerves consist of tightly packed axons and flattened, glial cell processes without significant extracellular space, matrix, or basal lamina. The glial cell bodies lie among the axons inside the nerve or at the nerve surface. These cells represent the first stage of the Schwann cell lineage, Schwann cell precursors (Figs. 3 and 4).

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“…In addition to the role of ERK1/2, recent data also indicate that the transcription factor Pax-3 has a role in differentiation and proliferation of Schwann cells after a peripheral nerve injury (Doddrell et al, 2012). Finally, and maybe of convincing importance, the transcription factor c-Jun, which is expressed in Schwann cells, seems to be a global regulator of the Wallerian degeneration process, since it may determine the expression of trophic factors, adhesion molecules, formation of regeneration tracks and myelin clearance as well as the control of distinct regenerative potential of the peripheral nerve.…”

Section: The Intrinsic Response In Neurons and Schwann Cells After Inmentioning

confidence: 99%

The Role of Timing in Nerve Reconstruction

Dahlin

2013

International Review of Neurobiology

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The surgeon, who treats nerve injuries, should have knowledge about how peripheral nerves react to trauma, particularly an understanding about the extensive pathophysiological alterations that occur both in the peripheral and in the central nervous system. A large number of factors influence the functional outcome, where the surgeon only can affect a few of them.In view of the new knowledge about the delicate intracellular signaling pathways that are rapidly initiated in neurons and in non-neuronal cells with the purpose to induce nerve regeneration, the timing of nerve repair and reconstruction after injury has gained more interest. It is crucial to understand and to utilize the inborn mechanisms for survival and regeneration of neurons and for activation, survival and proliferation of the Schwann cells and other cells that are acting after a nerve injury. Thus, experimental and clinical data clearly point towards the advantage of early nerve repair and reconstruction of injuries. Following an appropriate diagnosis of a nerve injury, the nerve should be promptly repaired or reconstructed, and new rehabilitation strategies should early be initiated. Considering nerve transfers in the treatment arsenal can shorten the time of nerve reinnervation of muscle targets. Timing of nerve repair and reconstruction is crucial after nerve injury.

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Regulation of Schwann cell differentiation and proliferation by the Pax‐3 transcription factor

Cited by 54 publications

References 61 publications

Pax genes: regulators of lineage specification and progenitor cell maintenance

Pax genes: regulators of lineage specification and progenitor cell maintenance

Schwann Cells: Development and Role in Nerve Repair

The Role of Timing in Nerve Reconstruction

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