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Review
. 2008 Dec;21(6):627-45.
doi: 10.1111/j.1755-148X.2008.00514.x.

Pigmentation PAX-ways: the role of Pax3 in melanogenesis, melanocyte stem cell maintenance, and disease

Jennifer D Kubic  1 , Kacey P Young, Rebecca S Plummer, Anton E Ludvik, Deborah Lang
Affiliations
Review

Pigmentation PAX-ways: the role of Pax3 in melanogenesis, melanocyte stem cell maintenance, and disease

Jennifer D Kubic et al. Pigment Cell Melanoma Res. 2008 Dec.

Abstract

Transcription factors initiate programs of gene expression and are catalysts in downstream molecular cascades that modulate a variety of cellular processes. Pax3 is a transcription factor that is important in the melanocyte and influences melanocytic proliferation, resistance to apoptosis, migration, lineage specificity and differentiation. In this review, we focus on Pax3 and the molecular pathways that Pax3 is a part of during melanogenesis and in the melanocyte stem cell. These roles of Pax3 are emphasized during the development of diseases and syndromes resulting from either too much or too little Pax3 function. Due to its key task in melanocyte stem cells and tumors, the Pax3 pathway may provide an ideal target for either stem cell or cancer therapies.

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Figures

Figure 1
Figure 1
The Pax3 protein has four domains: the paired domain, octapeptide motif, homeodomain and transactivation domain. A. The paired domain (lavender) is made of PAI- and RED- subdomains. PAI is composed of two beta-sheets and a helix turn helix (HTH) motif, while RED contains a HTH motif. The homeodomain (pink) possesses three helicies designated I, II and III. The transactivating domain (TA) is located in the C terminal tail of the protein. The octapeptide motif is yellow. N-terminal (N) and C-terminal are indicated. Numbers correspond to amino acid sequence. B. The amino acid sequence of canonical Pax3. Odd numbered exons are denoted with black font, blue represents even numbered exons. Grey amino acids have a codon shared by the two surrounding exons. Specific regions of the protein are highlighted; the paired domain (lavender), the octapeptide (yellow), and the homeodomain (pink).
Figure 2
Figure 2
Pax3 is expressed during development in the migrating neural crest and in other structures. A. Schematic of an E12.5 embryo. Approximate anatomic location of the area where the section shown in (B) is located is boxed on the picture. B. Pax3 expression in a section of E12.5 embryo. Immunofluorescence reveals Pax3 expression in a restricted pattern limited to the medial-dorsal area of the neural tube, the dorsal root ganglia, myotome-derived migrating primitive myoblasts, and migrating neural crest cells (white arrowheads). Boxed area is shown in detail in (C). C. Neural crest cells are migrating from a region dorsal to the neural tube and under the ectoderm (white arrows). D. Schematic of photo shown in (B). Pax3-expression domains are shown in green. The neural crest (NC) cells migrate in two major populations; dorso-ventral traveling cells (NC (dv)) and cells that travel mediolaterally (NC (ml)) dorsal to the dorsal root ganglia (DRG) and the somites or the myotome cells (M). This later population is generally fated to become melanocytes.
Figure 3
Figure 3
Canonical Wnt signaling affects downstream genes in melanogenesis. A. In the absence of Wnt signaling, Pax3, together with Sox10, can activate the expression of Mitf while simultaneously repressing Dct expression. Pax3 forms a transcriptional repressor complex with Lef1 and groucho-related proteins such as Grg4. There is also a Lef1 binding site in the Mitf promoter. B. Canonical Wnt signaling alters gene expression in melanocytes. Wnt signals activate beta-catenin (βcat) and, together with Lef1, upregulates expression of Mitf. Activated beta-catenin also forms an activator complex on the Dct promoter comprised of beta-catenin, Mitf, and Lef1 and displaces the repressor complex containing Pax3. Sox10 can also synergistically activate Dct with Mitf, and can bind to a site just 3' to the M site as well as several other sites further 5' of the enhancer region shown. Mitf can also activate other downstream targets either with Lef1 and beta-catenin (other loci A) or with beta-catenin alone (other loci B). For example, Mitf can activate both Tyrp1 and Tyrosinase with beta-catenin in the absence of Lef1. This figure is a summary of findings from several manuscripts (Lang et al., 2005, Schepsky et al., 2006, Takeda et al., 2000, Yasumoto et al., 2002, Jiao et al., 2004, Ludwig et al., 2004).
Figure 4
Figure 4
Summary of Pax3 function during melanocyte development and in the melanocyte stem cell. Cellular responses are listed, and examples of downstream targets regulating these traits are in parentheses. Protein binding partners, such as transcriptional coactivators and repressors as well as modifying proteins can inhibit or enhance the function of Pax3.
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