Pax3 regulates Wnt1 expression via a conserved binding site in the 5′ proximal promoter

Genes and Development Group, Centres for Integrative Physiology and Neuroscience Research, School of Biomedical Sciences, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh, EH8 9XD, UK.
Biochimica et Biophysica Acta (Impact Factor: 4.66). 03/2008; 1779(2):115-21. DOI: 10.1016/j.bbagrm.2007.11.008
Source: PubMed

ABSTRACT The development of the neural crest is orchestrated by a complex interplay between intercellular signalling molecules and transcription factors. Here, we demonstrate a direct interaction between two such factors, the paired-type transcription factor Pax3 and the secretory glycoprotein Wnt1. We found that the Wnt1 promoter can be regulated by Pax3 in a dose-dependent manner. Sequence analysis predicted a conserved binding site for Pax3 within the Wnt1 promoter region. Deletion or mutation of this sequence abolished the promoter response to Pax3. Using chromatin immunoprecipitation (ChIP) assays, we demonstrated that Pax3 interacts with the Wnt1 promoter in vivo. These data indicate that Pax3 directly regulates the expression of Wnt1 in the developing embryo.

  • Source
    • "Use of the classic Pax3 Sp and Pax3 Sp-d alleles confirms that we have uncovered a true genetic interaction rather than differences between Wnt1-Cre and Pax3 Cre expression domains, despite the fact that there are known differences in Cre expression in these two mouse lines (Engleka et al., 2005; Jiang et al., 2000). Pax3 is expressed before Wnt1 in the NC (Fenby et al., 2008; Osorio et al., 2009), and Pax3 binds directly to the Wnt1 promoter to activate Wnt1 transcription (Fenby et al., 2008), suggesting it is upstream. Wnt1-Cre is more commonly used for NC-specific deletion, but will act on cells within the developing roof plate and midbrain and does not label NCCs from the posterior-most levels of the NT (Jiang et al., 2000). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The transcription factors Foxd3 and Pax3 are important early regulators of neural crest (NC) progenitor cell properties. Homozygous mutations of Pax3 or a homozygous NC-specific deletion of Foxd3 cause marked defects in most NC derivatives, but neither loss of both Foxd3 alleles nor loss of one Pax3 allele alone greatly affects overall development of cardiac NC derivatives. In contrast, compound mutant embryos homozygous for a NC-specific Foxd3 mutation and heterozygous for Pax3 have fully penetrant persistent truncus arteriosus, severe thymus hypoplasia, and midgestation lethality. Foxd3; Pax3 compound mutant embryos have increased cell death in the neural folds and a drastic early reduction of NC cells, with an almost complete absence of NC caudal to the first pharyngeal arch. The genetic interaction between these genes implicates gene dosage-sensitive roles for Foxd3 and Pax3 in cardiac NC progenitors. Foxd3 and Pax3 act together to affect survival and maintenance of cardiac NC progenitors, and loss of these progenitors catastrophically affects key aspects of later cardiovascular development.
    genesis 01/2011; 49(1):10-23. DOI:10.1002/dvg.20686 · 2.04 Impact Factor
  • Source
    • "In line with this function, it regulates the expression of the muscle-specific TF, myoD, and myf-5 [Bajard et al., 2006; Bendall et al., 1999]. PAX3 also controls key regulators of NC development, such as c-RET, TGF-b2, and WNT1 [Fenby et al., 2008; Lang and Epstein, 2003; Mayanil et al., 2006]. The dependence on PAX3 function for proper NC development is highlighted by the phenotype induced by PAX3 mutations in human and mice. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Waardenburg syndrome (WS) is characterized by the association of pigmentation abnormalities, including depigmented patches of the skin and hair, vivid blue eyes or heterochromia irides, and sensorineural hearing loss. However, other features such as dystopia canthorum, musculoskeletal abnormalities of the limbs, Hirschsprung disease, or neurological defects are found in subsets of patients and used for the clinical classification of WS. Six genes are involved in this syndrome: PAX3 (encoding the paired box 3 transcription factor), MITF (microphthalmia-associated transcription factor), EDN3 (endothelin 3), EDNRB (endothelin receptor type B), SOX10 (encoding the Sry bOX10 transcription factor), and SNAI2 (snail homolog 2), with different frequencies. In this review we provide an update on all WS genes and set up mutation databases, summarize molecular and functional data available for each of them, and discuss the applications in diagnostics and genetic counseling. Hum Mutat 31, 1–16, 2010. © 2010 Wiley-Liss, Inc.
    Human Mutation 04/2010; 31(4):391 - 406. DOI:10.1002/humu.21211 · 5.05 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Pax transcription factors are critical for the development of the central nervous system (CNS) where they have a biphasic role, initially dictating CNS regionalization, while later orchestrating differentiation of specific cell subtypes. While a plethora of expression, misexpression, and mutation studies lend support for this argument and clarify the importance of Pax genes in CNS development, less well understood, and more perplexing, is the continued Pax expression in the adult CNS. In this article we explore the mechanism of action of Pax genes in general, and while being cognizant of existing developmental data, we also draw evidence from (1) adult progenitor cells involved in regeneration and tissue maintenance, (2) specific expression patterns in fully differentiated adult cells, and (3) analysis of direct target genes functioning downstream of Pax proteins. From this, we present a more encompassing theory that Pax genes are key regulators of a cell's measured response to a dynamic environment.
    Developmental Dynamics 10/2008; 237(10):2791-803. DOI:10.1002/dvdy.21711 · 2.67 Impact Factor
Show more