Krüppel-like Factor 4 is Involved in Functional Differentiation of Testicular Sertoli Cells

Overview

Journal Dev Biol

Publisher Elsevier

Specialties Biology
Reproductive Medicine

Date 2008 Feb 5

PMID 18243172

Citations 20

Authors

Maren Godmann

Jonathan P Katz

Florian Guillou

Manuela Simoni

Klaus H Kaestner

Rudiger Behr

Affiliations

Soon will be listed here.

Abstract

Krüppel-like factor 4 (KLF4) is a pleiotropic zinc finger transcription factor that regulates genes being involved in differentiation and cell-cycle control. Knockout studies revealed a critical function for KLF4 in the terminal differentiation of many epithelial cells. In testicular Sertoli cells, Klf4 is strongly inducible by the glycoprotein follicle stimulating hormone (FSH). Because KLF4 is essential for postnatal survival in mice, we deleted Klf4 specifically in Sertoli cells using the Cre/loxP system. Importantly, around postnatal day 18, a critical period of terminal Sertoli cell differentiation, mutant seminiferous tubules exhibited a disorganized germinal epithelium and delayed lumen formation. The ultrastructural finding of highly vacuolized Sertoli cell cytoplasm and the identification of differentially expressed genes, which are known to play roles during vesicle transport and fusion or for maintenance of the differentiated cell state, suggest impaired apical secretion of the Sertoli cell. Interestingly, a high proportion of all identified genes was localized in a small subregion of chromosome 7, suggesting coordinated regulation. Intriguingly, adult mutant mice are fertile and show normal testicular morphology, although the testosterone levels are decreased. In summary, KLF4 plays a significant role for proper and timely Sertoli cell differentiation in pubertal mice.

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References

Sairam M, Krishnamurthy H . The role of follicle-stimulating hormone in spermatogenesis: lessons from knockout animal models. Arch Med Res. 2001; 32(6):601-8. DOI: 10.1016/s0188-4409(01)00328-9. View

Gautam R, Chintala S, Li W, Zhang Q, Tan J, Novak E . The Hermansky-Pudlak syndrome 3 (cocoa) protein is a component of the biogenesis of lysosome-related organelles complex-2 (BLOC-2). J Biol Chem. 2004; 279(13):12935-42. DOI: 10.1074/jbc.M311311200. View

Sylvester S, Griswold M . The testicular iron shuttle: a "nurse" function of the Sertoli cells. J Androl. 1994; 15(5):381-5. View

Lindfors K, Halttunen T, Kainulainen H, Maki M . Differentially expressed CC3/TIP30 and rab11 along in vivo and in vitro intestinal epithelial cell crypt-villus axis. Life Sci. 2001; 69(12):1363-72. DOI: 10.1016/s0024-3205(01)01216-4. View

Lecureuil C, Fontaine I, Crepieux P, Guillou F . Sertoli and granulosa cell-specific Cre recombinase activity in transgenic mice. Genesis. 2002; 33(3):114-8. DOI: 10.1002/gene.10100. View

Schmahl J, Eicher E, Washburn L, Capel B . Sry induces cell proliferation in the mouse gonad. Development. 2000; 127(1):65-73. DOI: 10.1242/dev.127.1.65. View

Wei M . Hermansky-Pudlak syndrome: a disease of protein trafficking and organelle function. Pigment Cell Res. 2006; 19(1):19-42. DOI: 10.1111/j.1600-0749.2005.00289.x. View

Okita K, Ichisaka T, Yamanaka S . Generation of germline-competent induced pluripotent stem cells. Nature. 2007; 448(7151):313-7. DOI: 10.1038/nature05934. View

Shields J, Yang V . Identification of the DNA sequence that interacts with the gut-enriched Krüppel-like factor. Nucleic Acids Res. 1998; 26(3):796-802. PMC: 147321. DOI: 10.1093/nar/26.3.796. View

10.

Rowland B, Bernards R, Peeper D . The KLF4 tumour suppressor is a transcriptional repressor of p53 that acts as a context-dependent oncogene. Nat Cell Biol. 2005; 7(11):1074-82. DOI: 10.1038/ncb1314. View

11.

Jiang C, Xuan Z, Zhao F, Zhang M . TRED: a transcriptional regulatory element database, new entries and other development. Nucleic Acids Res. 2007; 35(Database issue):D137-40. PMC: 1899102. DOI: 10.1093/nar/gkl1041. View

12.

Ito M, Jiang C, Krumm K, Zhang X, Pecha J, Zhao J . TIP30 deficiency increases susceptibility to tumorigenesis. Cancer Res. 2003; 63(24):8763-7. View

13.

De Gendt K, Swinnen J, Saunders P, Schoonjans L, Dewerchin M, Devos A . A Sertoli cell-selective knockout of the androgen receptor causes spermatogenic arrest in meiosis. Proc Natl Acad Sci U S A. 2004; 101(5):1327-32. PMC: 337052. DOI: 10.1073/pnas.0308114100. View

14.

Foster K, Liu Z, Nail C, Li X, Fitzgerald T, Bailey S . Induction of KLF4 in basal keratinocytes blocks the proliferation-differentiation switch and initiates squamous epithelial dysplasia. Oncogene. 2005; 24(9):1491-500. PMC: 1361530. DOI: 10.1038/sj.onc.1208307. View

15.

Chen X, Whitney E, Gao S, Yang V . Transcriptional profiling of Krüppel-like factor 4 reveals a function in cell cycle regulation and epithelial differentiation. J Mol Biol. 2003; 326(3):665-77. PMC: 2693487. DOI: 10.1016/s0022-2836(02)01449-3. View

16.

Hummler E, Cole T, Blendy J, Ganss R, Aguzzi A, Schmid W . Targeted mutation of the CREB gene: compensation within the CREB/ATF family of transcription factors. Proc Natl Acad Sci U S A. 1994; 91(12):5647-51. PMC: 44053. DOI: 10.1073/pnas.91.12.5647. View

17.

Bailey R, Aronow B, Harmony J, Griswold M . Heat shock-initiated apoptosis is accelerated and removal of damaged cells is delayed in the testis of clusterin/ApoJ knock-out mice. Biol Reprod. 2002; 66(4):1042-53. DOI: 10.1095/biolreprod66.4.1042. View

18.

Behr R, Kaestner K . Developmental and cell type-specific expression of the zinc finger transcription factor Krüppel-like factor 4 (Klf4) in postnatal mouse testis. Mech Dev. 2002; 115(1-2):167-9. DOI: 10.1016/s0925-4773(02)00127-2. View

19.

Takahashi K, Yamanaka S . Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006; 126(4):663-76. DOI: 10.1016/j.cell.2006.07.024. View

20.

Chang C, Chen Y, Yeh S, Xu Q, Wang R, Guillou F . Infertility with defective spermatogenesis and hypotestosteronemia in male mice lacking the androgen receptor in Sertoli cells. Proc Natl Acad Sci U S A. 2004; 101(18):6876-81. PMC: 406435. DOI: 10.1073/pnas.0307306101. View