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The transcription factor Sox5 modulates Sox10 function during melanocyte development.

Stolt CC, Lommes P, Hillgärtner S, Wegner M - Nucleic Acids Res. (2008)

Bottom Line: The transcription factor Sox5 has previously been shown in chicken to be expressed in early neural crest cells and neural crest-derived peripheral glia.This modulatory activity involved Sox5 binding and recruitment of CtBP2 and HDAC1 to the regulatory regions of melanocytic Sox10 target genes and direct inhibition of Sox10-dependent promoter activation.Both binding site competition and recruitment of corepressors thus help Sox5 to modulate the activity of Sox10 in the melanocyte lineage.

View Article: PubMed Central - PubMed

Affiliation: Institut für Biochemie, Emil-Fischer-Zentrum, Universität Erlangen, Fahrstrasse 17, D-91054 Erlangen, Germany.

ABSTRACT
The transcription factor Sox5 has previously been shown in chicken to be expressed in early neural crest cells and neural crest-derived peripheral glia. Here, we show in mouse that Sox5 expression also continues after neural crest specification in the melanocyte lineage. Despite its continued expression, Sox5 has little impact on melanocyte development on its own as generation of melanoblasts and melanocytes is unaltered in Sox5-deficient mice. Loss of Sox5, however, partially rescued the strongly reduced melanoblast generation and marker gene expression in Sox10 heterozygous mice arguing that Sox5 functions in the melanocyte lineage by modulating Sox10 activity. This modulatory activity involved Sox5 binding and recruitment of CtBP2 and HDAC1 to the regulatory regions of melanocytic Sox10 target genes and direct inhibition of Sox10-dependent promoter activation. Both binding site competition and recruitment of corepressors thus help Sox5 to modulate the activity of Sox10 in the melanocyte lineage.

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Melanoblast development in embryos with Sox5 deficiency and/or Sox10 heterozygosity. (A–P) Whole-mount in situ hybridizations were performed on wild-type (A, E, I and M), Sox5−/− (B, F, J and N), Sox10+/lacZ (C, G, K and O) and Sox5−/−, Sox10+/lacZ (D, H, L and P) embryos at 10.5 dpc using antisense riboprobes against c-Kit (A–H), Dct (I–L) and Mitf (M–P). Results for c-Kit are shown both in low (A–D) and high (E–H) magnification with the magnified region boxed in the overviews. For Dct and Mitf, only high magnifications from the forelimb area are shown. (Q and R) Total Dct- (Q) and Mitf-positive cells (R) were quantified in age-matched wild-type, Sox5−/− and Sox10+/lacZ embryos as well as their Sox5−/−, Sox10+/lacZ littermates. Six embryos were counted for each genotype. The number of cells counted per embryo is presented as mean ± standard deviation. Cell numbers for the Sox5−/− genotype were comparable to the wild-type, whereas dramatic reductions were observed for the Sox10+/lacZ embryos. The difference in cell counts between the Sox5−/−, Sox10+/lacZ embryos and the Sox10+/lacZ embryos were statistically significant as determined by Student's t-test (**P ⩽ 0.01).
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Figure 3: Melanoblast development in embryos with Sox5 deficiency and/or Sox10 heterozygosity. (A–P) Whole-mount in situ hybridizations were performed on wild-type (A, E, I and M), Sox5−/− (B, F, J and N), Sox10+/lacZ (C, G, K and O) and Sox5−/−, Sox10+/lacZ (D, H, L and P) embryos at 10.5 dpc using antisense riboprobes against c-Kit (A–H), Dct (I–L) and Mitf (M–P). Results for c-Kit are shown both in low (A–D) and high (E–H) magnification with the magnified region boxed in the overviews. For Dct and Mitf, only high magnifications from the forelimb area are shown. (Q and R) Total Dct- (Q) and Mitf-positive cells (R) were quantified in age-matched wild-type, Sox5−/− and Sox10+/lacZ embryos as well as their Sox5−/−, Sox10+/lacZ littermates. Six embryos were counted for each genotype. The number of cells counted per embryo is presented as mean ± standard deviation. Cell numbers for the Sox5−/− genotype were comparable to the wild-type, whereas dramatic reductions were observed for the Sox10+/lacZ embryos. The difference in cell counts between the Sox5−/−, Sox10+/lacZ embryos and the Sox10+/lacZ embryos were statistically significant as determined by Student's t-test (**P ⩽ 0.01).

Mentions: Taking the widespread expression in melanoblasts into account, we next asked whether loss of Sox5 would influence the early stages of melanocytic development. Whole-mount in situ hybridizations were performed on Sox5−/− embryos at 10.5 and 11.5 dpc to follow melanoblast development and results were compared with age-matched wild-types (Figure 3 and data not shown). Care was taken that analyzed embryos throughout our studies were in a very similar stage of development and had a comparable genetic background. Using c-Kit, Dct and Mitf as three independent markers of the early melanocyte lineage, we failed to detect any significant difference in the appearance or migration pattern of melanoblasts in Sox5−/− embryos (compare Figure 3A, E, I and M to Figure 3B, F, J and N). Melanoblast numbers were also comparable between Sox5−/− embryos and their wild-type littermates (Figure 3Q and R). The fact that the absolute number of melanoblasts was twice as high with Dct as with Mitf as probe, simply reflects the different sensitivities of the respective probes. Distribution and number of melanocytes were also normal in Sox5−/− mice at the time of birth (data not shown). Our analyses thus revealed that Sox5 is dispensable for specification of melanoblasts and the consecutive phases of melanocyte development.Figure 3.


The transcription factor Sox5 modulates Sox10 function during melanocyte development.

Stolt CC, Lommes P, Hillgärtner S, Wegner M - Nucleic Acids Res. (2008)

Melanoblast development in embryos with Sox5 deficiency and/or Sox10 heterozygosity. (A–P) Whole-mount in situ hybridizations were performed on wild-type (A, E, I and M), Sox5−/− (B, F, J and N), Sox10+/lacZ (C, G, K and O) and Sox5−/−, Sox10+/lacZ (D, H, L and P) embryos at 10.5 dpc using antisense riboprobes against c-Kit (A–H), Dct (I–L) and Mitf (M–P). Results for c-Kit are shown both in low (A–D) and high (E–H) magnification with the magnified region boxed in the overviews. For Dct and Mitf, only high magnifications from the forelimb area are shown. (Q and R) Total Dct- (Q) and Mitf-positive cells (R) were quantified in age-matched wild-type, Sox5−/− and Sox10+/lacZ embryos as well as their Sox5−/−, Sox10+/lacZ littermates. Six embryos were counted for each genotype. The number of cells counted per embryo is presented as mean ± standard deviation. Cell numbers for the Sox5−/− genotype were comparable to the wild-type, whereas dramatic reductions were observed for the Sox10+/lacZ embryos. The difference in cell counts between the Sox5−/−, Sox10+/lacZ embryos and the Sox10+/lacZ embryos were statistically significant as determined by Student's t-test (**P ⩽ 0.01).
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Figure 3: Melanoblast development in embryos with Sox5 deficiency and/or Sox10 heterozygosity. (A–P) Whole-mount in situ hybridizations were performed on wild-type (A, E, I and M), Sox5−/− (B, F, J and N), Sox10+/lacZ (C, G, K and O) and Sox5−/−, Sox10+/lacZ (D, H, L and P) embryos at 10.5 dpc using antisense riboprobes against c-Kit (A–H), Dct (I–L) and Mitf (M–P). Results for c-Kit are shown both in low (A–D) and high (E–H) magnification with the magnified region boxed in the overviews. For Dct and Mitf, only high magnifications from the forelimb area are shown. (Q and R) Total Dct- (Q) and Mitf-positive cells (R) were quantified in age-matched wild-type, Sox5−/− and Sox10+/lacZ embryos as well as their Sox5−/−, Sox10+/lacZ littermates. Six embryos were counted for each genotype. The number of cells counted per embryo is presented as mean ± standard deviation. Cell numbers for the Sox5−/− genotype were comparable to the wild-type, whereas dramatic reductions were observed for the Sox10+/lacZ embryos. The difference in cell counts between the Sox5−/−, Sox10+/lacZ embryos and the Sox10+/lacZ embryos were statistically significant as determined by Student's t-test (**P ⩽ 0.01).
Mentions: Taking the widespread expression in melanoblasts into account, we next asked whether loss of Sox5 would influence the early stages of melanocytic development. Whole-mount in situ hybridizations were performed on Sox5−/− embryos at 10.5 and 11.5 dpc to follow melanoblast development and results were compared with age-matched wild-types (Figure 3 and data not shown). Care was taken that analyzed embryos throughout our studies were in a very similar stage of development and had a comparable genetic background. Using c-Kit, Dct and Mitf as three independent markers of the early melanocyte lineage, we failed to detect any significant difference in the appearance or migration pattern of melanoblasts in Sox5−/− embryos (compare Figure 3A, E, I and M to Figure 3B, F, J and N). Melanoblast numbers were also comparable between Sox5−/− embryos and their wild-type littermates (Figure 3Q and R). The fact that the absolute number of melanoblasts was twice as high with Dct as with Mitf as probe, simply reflects the different sensitivities of the respective probes. Distribution and number of melanocytes were also normal in Sox5−/− mice at the time of birth (data not shown). Our analyses thus revealed that Sox5 is dispensable for specification of melanoblasts and the consecutive phases of melanocyte development.Figure 3.

Bottom Line: The transcription factor Sox5 has previously been shown in chicken to be expressed in early neural crest cells and neural crest-derived peripheral glia.This modulatory activity involved Sox5 binding and recruitment of CtBP2 and HDAC1 to the regulatory regions of melanocytic Sox10 target genes and direct inhibition of Sox10-dependent promoter activation.Both binding site competition and recruitment of corepressors thus help Sox5 to modulate the activity of Sox10 in the melanocyte lineage.

View Article: PubMed Central - PubMed

Affiliation: Institut für Biochemie, Emil-Fischer-Zentrum, Universität Erlangen, Fahrstrasse 17, D-91054 Erlangen, Germany.

ABSTRACT
The transcription factor Sox5 has previously been shown in chicken to be expressed in early neural crest cells and neural crest-derived peripheral glia. Here, we show in mouse that Sox5 expression also continues after neural crest specification in the melanocyte lineage. Despite its continued expression, Sox5 has little impact on melanocyte development on its own as generation of melanoblasts and melanocytes is unaltered in Sox5-deficient mice. Loss of Sox5, however, partially rescued the strongly reduced melanoblast generation and marker gene expression in Sox10 heterozygous mice arguing that Sox5 functions in the melanocyte lineage by modulating Sox10 activity. This modulatory activity involved Sox5 binding and recruitment of CtBP2 and HDAC1 to the regulatory regions of melanocytic Sox10 target genes and direct inhibition of Sox10-dependent promoter activation. Both binding site competition and recruitment of corepressors thus help Sox5 to modulate the activity of Sox10 in the melanocyte lineage.

Show MeSH
Related in: MedlinePlus