Transcriptional regulation by Pax3 and TGFbeta2 signaling: a potential gene regulatory network in neural crest development

Nakazaki, Hiromichi; Shen, Yueh-Wei; Yun, Beth; Reddy, Anvesh C.; Khanna, Varun; Mania-Farnell, Barbara; Ichi, Shunsuke; McLone, David G.; Tomita, Tadanori; Mayanil, C. Shekhar

doi:10.1387/ijdb.082682hn

Cited by 10 publications

(11 citation statements)

References 54 publications

(80 reference statements)

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“…Results were attributed to the opposing roles of PAX3 and TGFβ2 in the regulation of Hes1, Neurog2 and Sox9, as seen in earlier studies (Mayanil et al, 2001;Zavadil et al, 2001). Following this, a model was described in which the regulatory network between Pax3, Tgfb2, Hes1, Neurog2 and Sox9 functions to maintain NC cells in an undifferentiated state prior to migration while ensuring progenitor cell identity is specified through appropriate timing of Hes1, Neurog2 and Sox9 expression (Nakazaki et al, 2009). …”

Section: Pax3cmentioning

confidence: 89%

“…Pax3 also regulates Hes1 (hairy and enhancer of split 1; which is involved in neural stem cell maintenance), Neurog2 (which is involved in NC neurogenesis) and Tgfb2 (transforming growth factor β2) (which in turn represses Pax3 promoter activity on Hes1 and Neurog2) (Theriault et al, 2005;Mayanil et al, 2006;Nakazaki et al, 2008;Medic and Ziman, 2010). Using mice bred for a double heterozygous Pax3 and Tgfb2 phenotype, Nakazaki et al (Nakazaki et al, 2009) ). Results were attributed to the opposing roles of PAX3 and TGFβ2 in the regulation of Hes1, Neurog2 and Sox9, as seen in earlier studies (Mayanil et al, 2001;Zavadil et al, 2001).…”

Section: Pax3cmentioning

confidence: 99%

“…Nakazaki et al also discussed a possible role for Pax3 and Tgfb2 in remodelling of the extracellular matrix to facilitate NC cell migration (Nakazaki et al, 2009); however, the continuing Uses an alternate in-frame splice site compared with variant 1. The resulting isoform has the same N and C termini but is two amino acids shorter than variant 1.…”

Section: Pax3cmentioning

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: Pax3cmentioning

confidence: 89%

Section: Pax3cmentioning

confidence: 99%

Section: Pax3cmentioning

confidence: 99%

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Pax genes: regulators of lineage specification and progenitor cell maintenance

2014

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“…Also, besides inhibiting BMP type I receptors (also known as ALK receptors), dorsomorphin inhibits the activity of various other kinases and, hence, modulates cell physiology through many signaling pathways (Vogt et al, 2011). In addition, we did not block the activin-TGF-b pathway with SB431542, because this pathway has been shown to be crucial for neural crest differentiation and proliferation (Nakazaki et al, 2009;Wurdak et al, 2005). Secondly, we used N2B27, not only N2, as an additive to the basal medium.…”

Section: Discussionmentioning

confidence: 99%

Notch signaling regulates neural crest differentiation from human pluripotent stem cells

Noisa

Lund

Kanduri

et al. 2014

Journal of Cell Science

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Neural crest (NC) cells are specified at the border of neural plate and epiderm. They are capable of differentiating into various somatic cell types, including craniofacial and peripheral nerve tissues. Notch signaling plays significant roles during neurogenesis; however, its function during human NC development is poorly understood. Here, we generated self-renewing premigratory NC-like cells (pNCCs) from human pluripotent stem cells and investigated the roles of Notch signaling during the NC differentiation. pNCCs expressed various NC specifier genes, including SLUG, SOX10 and TWIST1, and were able to differentiate into most NC derivatives. Blocking Notch signaling during the pNCC differentiation suppressed the expression of NC specifier genes. In contrast, ectopic expression of activated Notch1 intracellular domain (NICD1) augmented the expression of NC specifier genes, and NICD1 was found to bind at their promoter regions. Notch activity was also required for the maintenance of premigratory NC state, and suppression of Notch led to generation of NC-derived neurons. Taken together, we provide a protocol for the generation of pNCCs, and show that Notch signaling regulates the formation, migration and differentiation of NC from hPSCs.

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“…Other transcription factors, such as p53 and activated estrogen receptor ␣, have been shown to play a role in miRNA biogenesis and maturation (25,26). It is plausible that during development, the Pax3 transcription factor can have a dual function of regulating target genes at transcriptional (13,(27)(28)(29) and post-transcriptional levels.…”

Section: Discussionmentioning

confidence: 99%