C/EBPalpha and C/EBPbeta Are Required for Sebocyte Differentiation and Stratified Squamous Differentiation in Adult Mouse Skin

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2010 Mar 31

PMID 20352127

Citations 24

Authors

John S House

Songyun Zhu

Rakesh Ranjan

Keith Linder

Robert C Smart

Affiliations

Soon will be listed here.

Abstract

C/EBPalpha and C/EBPbeta are bZIP transcription factors that are highly expressed in the interfollicular epidermis and sebaceous glands of skin and yet germ line deletion of either family member alone has only mild or no effect on keratinocyte biology and their role in sebocyte biology has never been examined. To address possible functional redundancies and reveal functional roles of C/EBPalpha and C/EBPbeta in postnatal skin, mouse models were developed in which either family member could be acutely ablated alone or together in the epidermis and sebaceous glands of adult mice. Acute removal of either C/EBPalpha or C/EBPbeta alone in adult mouse skin revealed modest to no discernable changes in epidermis or sebaceous glands. In contrast, co-ablation of C/EBPalpha and C/EBPbeta in postnatal epidermis resulted in disruption of stratified squamous differentiation characterized by hyperproliferation of basal and suprabasal keratinocytes and a defective basal to spinous keratinocyte transition involving an expanded basal compartment and a diminished and delayed spinous compartment. Acute co-ablation of C/EBPalpha and C/EBPbeta in sebaceous glands resulted in severe morphological defects, and sebocyte differentiation was blocked as determined by lack of sebum production and reduced expression of stearoyl-CoA desaturase (SCD3) and melanocortin 5 receptor (MC5R), two markers of terminal sebocyte differentiation. Specialized sebocytes of Meibomian glands and preputial glands were also affected. Our results indicate that in adult mouse skin, C/EBPalpha and C/EBPbeta are critically involved in regulating sebocyte differentiation and epidermal homeostasis involving the basal to spinous keratinocyte transition and basal cell cycle withdrawal.

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References

Katz S, Kowenz-Leutz E, Muller C, Meese K, Ness S, Leutz A . The NF-M transcription factor is related to C/EBP beta and plays a role in signal transduction, differentiation and leukemogenesis of avian myelomonocytic cells. EMBO J. 1993; 12(4):1321-32. PMC: 413343. DOI: 10.1002/j.1460-2075.1993.tb05777.x. View

Robinson G, Johnson P, Hennighausen L, Sterneck E . The C/EBPbeta transcription factor regulates epithelial cell proliferation and differentiation in the mammary gland. Genes Dev. 1998; 12(12):1907-16. PMC: 316915. DOI: 10.1101/gad.12.12.1907. View

Sterneck E, Zhu S, Ramirez A, Jorcano J, Smart R . Conditional ablation of C/EBP beta demonstrates its keratinocyte-specific requirement for cell survival and mouse skin tumorigenesis. Oncogene. 2005; 25(8):1272-1276. PMC: 3773579. DOI: 10.1038/sj.onc.1209144. View

Loomis K, Zhu S, Yoon K, Johnson P, Smart R . Genetic ablation of CCAAT/enhancer binding protein alpha in epidermis reveals its role in suppression of epithelial tumorigenesis. Cancer Res. 2007; 67(14):6768-76. PMC: 3773581. DOI: 10.1158/0008-5472.CAN-07-0139. View

Friedman A, Landschulz W, McKnight S . CCAAT/enhancer binding protein activates the promoter of the serum albumin gene in cultured hepatoma cells. Genes Dev. 1989; 3(9):1314-22. DOI: 10.1101/gad.3.9.1314. View

Jones L, Lin M, Chen S, Krug U, Hofmann W, Lee S . Expression of C/EBPbeta from the C/ebpalpha gene locus is sufficient for normal hematopoiesis in vivo. Blood. 2002; 99(6):2032-6. DOI: 10.1182/blood.v99.6.2032. View

Chen W, Yang C, Sheu H, Seltmann H, Zouboulis C . Expression of peroxisome proliferator-activated receptor and CCAAT/enhancer binding protein transcription factors in cultured human sebocytes. J Invest Dermatol. 2003; 121(3):441-7. DOI: 10.1046/j.1523-1747.2003.12411.x. View

Chen S, Chen J, Johnson P, Muppala V, Lee Y . C/EBPbeta, when expressed from the C/ebpalpha gene locus, can functionally replace C/EBPalpha in liver but not in adipose tissue. Mol Cell Biol. 2000; 20(19):7292-9. PMC: 86283. DOI: 10.1128/MCB.20.19.7292-7299.2000. View

Cao Z, Umek R, McKnight S . Regulated expression of three C/EBP isoforms during adipose conversion of 3T3-L1 cells. Genes Dev. 1991; 5(9):1538-52. DOI: 10.1101/gad.5.9.1538. View

10.

Rangarajan A, Talora C, Okuyama R, Nicolas M, Mammucari C, Oh H . Notch signaling is a direct determinant of keratinocyte growth arrest and entry into differentiation. EMBO J. 2001; 20(13):3427-36. PMC: 125257. DOI: 10.1093/emboj/20.13.3427. View

11.

Zhang D, Zhang P, Wang N, Hetherington C, Darlington G, Tenen D . Absence of granulocyte colony-stimulating factor signaling and neutrophil development in CCAAT enhancer binding protein alpha-deficient mice. Proc Natl Acad Sci U S A. 1997; 94(2):569-74. PMC: 19554. DOI: 10.1073/pnas.94.2.569. View

12.

Seagroves T, Krnacik S, Raught B, Gay J, Burgess-Beusse B, Darlington G . C/EBPbeta, but not C/EBPalpha, is essential for ductal morphogenesis, lobuloalveolar proliferation, and functional differentiation in the mouse mammary gland. Genes Dev. 1998; 12(12):1917-28. PMC: 316914. DOI: 10.1101/gad.12.12.1917. View

13.

Wang N, Finegold M, Bradley A, Ou C, Abdelsayed S, Wilde M . Impaired energy homeostasis in C/EBP alpha knockout mice. Science. 1995; 269(5227):1108-12. DOI: 10.1126/science.7652557. View

14.

Lo Celso C, Berta M, Braun K, Frye M, Lyle S, Zouboulis C . Characterization of bipotential epidermal progenitors derived from human sebaceous gland: contrasting roles of c-Myc and beta-catenin. Stem Cells. 2008; 26(5):1241-52. DOI: 10.1634/stemcells.2007-0651. View

15.

Zhu S, Yoon K, Sterneck E, Johnson P, Smart R . CCAAT/enhancer binding protein-beta is a mediator of keratinocyte survival and skin tumorigenesis involving oncogenic Ras signaling. Proc Natl Acad Sci U S A. 2002; 99(1):207-12. PMC: 117540. DOI: 10.1073/pnas.012437299. View

16.

Johnson P . Molecular stop signs: regulation of cell-cycle arrest by C/EBP transcription factors. J Cell Sci. 2005; 118(Pt 12):2545-55. DOI: 10.1242/jcs.02459. View

17.

Umek R, Friedman A, McKnight S . CCAAT-enhancer binding protein: a component of a differentiation switch. Science. 1991; 251(4991):288-92. DOI: 10.1126/science.1987644. View

18.

Arnold I, Watt F . c-Myc activation in transgenic mouse epidermis results in mobilization of stem cells and differentiation of their progeny. Curr Biol. 2001; 11(8):558-68. DOI: 10.1016/s0960-9822(01)00154-3. View

19.

Sterneck E, Tessarollo L, Johnson P . An essential role for C/EBPbeta in female reproduction. Genes Dev. 1997; 11(17):2153-62. PMC: 275394. DOI: 10.1101/gad.11.17.2153. View

20.

Ramji D, Foka P . CCAAT/enhancer-binding proteins: structure, function and regulation. Biochem J. 2002; 365(Pt 3):561-75. PMC: 1222736. DOI: 10.1042/BJ20020508. View