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IκB kinase-α acts in the epidermis to control skeletal and craniofacial morphogenesis

Abstract

IκB kinase-α (IKK-α)1 exhibits protein-kinase-dependent and -independent functions. Its kinase activity is required for lymphoid organogenesis2 and mammary gland development3, whereas a kinase-independent activity is required for epidermal keratinocyte differentiation4. In addition to failed epidermal differentiation, IKK-α-deficient mice exhibit abnormal skeletal and craniofacial morphogenesis4,5,6. As similar defects are not exhibited by mice that experience systemic inhibition of NF-κB7, we postulated that the morphogenetic defects in IKK-α-deficient mice are not caused by reduced NF-κB activity but instead are due to failed epidermal differentiation that disrupts proper epidermal–mesodermal interactions. We tested this hypothesis by introducing an epidermal-specific Ikka (also known as Chuk) transgene into IKK-α-deficient mice. Mice lacking IKK-α in all cell types including bone and cartilage, but not in basal epidermal keratinocytes, exhibit normal epidermal differentiation and skeletal morphology. Thus, epidermal differentiation is required for proper morphogenesis of mesodermally derived skeletal elements. One way by which IKK-α controls skeletal and craniofacial morphogenesis is by repressing expression of fibroblast growth factor (FGF) family members, such as FGF8, whose expression is specifically elevated in the limb bud ectoderm of IKK-α-deficient mice.

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Figure 1: The CK14Ikka transgene restores normal physical appearance to Ikka-/- mice.
Figure 2: The CK14Ikka transgene rescues skin as well as craniofacial and skeletal defects of Ikka-/- mice.
Figure 3: Elevated FGF mRNA expression in Ikka-/- fetal limbs.
Figure 4: FGFR inhibitor rescues digitation in Ikka-/- limb buds.
Figure 5: IKK-α acts within the nucleus to induce keratinocyte differentiation.

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Acknowledgements

We thank A. Ullrich for the FGF receptor inhibitor (SU5402), T. Kato, M. Delhase and S. Roy for technical assistance and discussions, and M. Ellisman and M. Mackey for the election microscopy performed at the National Center for Microscopy and Imaging Research. Work was supported by grants from the National Institutes of Health, and Superfund Basic Research Program and CERIES research awards.

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Correspondence to Michael Karin.

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Supplementary information

Supplementary Figure 1

Comparison of transgenic hIKKα (tg IKKa ) expression with that of endogenous mIKKα. (PDF 23 kb)

Supplementary Figure 2

CK14-Ikka is not expressed in the esophagus. (PDF 164 kb)

Supplementary Figure 3

Defective epidermal differentiation of Ikka-/-mice is rescued by a CK14-Ikka(KM) transgene. (PDF 149 kb)

Supplementary Figure 4

The limbs and skeletal defects of Ikka-/- mice are rescued by CK14-Ikka transgene. (PDF 75 kb)

Supplementary Figure 5

The defect in craniofacial morphogenesis of Ikka-/- mice is rescued in Ikka-/-CK14-Ikka or Ikka-/-CK14-Ikka(KM) mice. (PDF 165 kb)

Supplementary Figure 6

FGF expression is reduced during keratinocyte differentiation. (PDF 196 kb)

Supplementary Figure Legends (DOC 22 kb)

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Sil, A., Maeda, S., Sano, Y. et al. IκB kinase-α acts in the epidermis to control skeletal and craniofacial morphogenesis. Nature 428, 660–664 (2004). https://doi.org/10.1038/nature02421

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