This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Plikus, M. Articles by Chuong, C.-M. Search for Related Content PubMed PubMed Citation Articles by Plikus, M. Articles by Chuong, C.-M.

(American Journal of Pathology. 2004;164:1099-1114.)
© 2004 American Society for Investigative Pathology

Animal Model

Morpho-Regulation of Ectodermal Organs

Integument Pathology and Phenotypic Variations in K14-Noggin Engineered Mice through Modulation of Bone Morphogenic Protein Pathway

Maksim Plikus^*, Wen Pin Wang^*, Jian Liu^*, Xia Wang^*, Ting-Xin Jiang^* and Cheng-Ming Chuong^*

From the Department of Pathology,^* Keck School of Medicine, University of Southern California, Los Angeles, California; and the Graduate Institute of Molecular and Cellular Biology, Tzu Chi University, Hualien, Taiwan

Ectodermal organs are composed of keratinocytes organized in different ways during induction, morphogenesis, differentiation, and regenerative stages. We hypothesize that an imbalance of fundamental signaling pathways should affect multiple ectodermal organs in a spatio-temporal-dependent manner. We produced a K14-Noggin transgenic mouse to modulate bone morphogenic protein (BMP) activity and test the extent of this hypothesis. We observed thickened skin epidermis, increased hair density, altered hair types, faster anagen re-entry, and formation of compound vibrissa follicles. The eyelid opening was smaller and ectopic cilia formed at the expense of Meibomian glands. In the distal limb, there were agenesis and hyperpigmentation of claws, interdigital webbing, reduced footpads, and trans-differentiation of sweat glands into hairs. The size of external genitalia increased in both sexes, but they remained fertile. We conclude that modulation of BMP activity can affect the number of ectodermal organs by acting during induction stages, influence the size and shape by acting during morphogenesis stages, change phenotypes by acting during differentiation stages, and facilitate new growth by acting during regeneration stages. Therefore during organogenesis, BMP antagonists can produce a spectrum of phenotypes in a stage-dependent manner by adjusting the level of BMP activity. The distinction between phenotypic variations and pathological changes is discussed.

This article has been cited by other articles:

				A. A. Sharov, A. N. Mardaryev, T. Y. Sharova, M. Grachtchouk, R. Atoyan, H. R. Byers, J. T. Seykora, P. Overbeek, A. Dlugosz, and V. A. Botchkarev Bone Morphogenetic Protein Antagonist Noggin Promotes Skin Tumorigenesis via Stimulation of the Wnt and Shh Signaling Pathways Am. J. Pathol., September 1, 2009; 175(3): 1303 - 1314. [Abstract] [Full Text] [PDF]

				J. Huang, L. K. Dattilo, R. Rajagopal, Y. Liu, V. Kaartinen, Y. Mishina, C.-X. Deng, L. Umans, A. Zwijsen, A. B. Roberts, et al. FGF-regulated BMP signaling is required for eyelid closure and to specify conjunctival epithelial cell fate Development, May 15, 2009; 136(10): 1741 - 1750. [Abstract] [Full Text] [PDF]

				J. A. Mayer, J. Foley, D. De La Cruz, C.-M. Chuong, and R. Widelitz Conversion of the Nipple to Hair-Bearing Epithelia by Lowering Bone Morphogenetic Protein Pathway Activity at the Dermal-Epidermal Interface Am. J. Pathol., November 1, 2008; 173(5): 1339 - 1348. [Abstract] [Full Text] [PDF]

				K. Narhi, E. Jarvinen, W. Birchmeier, M. M. Taketo, M. L. Mikkola, and I. Thesleff Sustained epithelial {beta}-catenin activity induces precocious hair development but disrupts hair follicle down-growth and hair shaft formation Development, March 15, 2008; 135(6): 1019 - 1028. [Abstract] [Full Text] [PDF]

				J. L. Rinn, J. K. Wang, N. Allen, S. A. Brugmann, A. J. Mikels, H. Liu, T. W. Ridky, H. S. Stadler, R. Nusse, J. A. Helms, et al. A dermal HOX transcriptional program regulates site-specific epidermal fate Genes & Dev., February 1, 2008; 22(3): 303 - 307. [Abstract] [Full Text] [PDF]

				S. Sick, S. Reinker, J. Timmer, and T. Schlake WNT and DKK Determine Hair Follicle Spacing Through a Reaction-Diffusion Mechanism Science, December 1, 2006; 314(5804): 1447 - 1450. [Abstract] [Full Text] [PDF]

				A. A. Sharov, T. Y. Sharova, A. N. Mardaryev, A. T. di Vignano, R. Atoyan, L. Weiner, S. Yang, J. L. Brissette, G. P. Dotto, and V. A. Botchkarev Bone morphogenetic protein signaling regulates the size of hair follicles and modulates the expression of cell cycle-associated genes PNAS, November 28, 2006; 103(48): 18166 - 18171. [Abstract] [Full Text] [PDF]

				U. Ohnemus, M. Uenalan, J. Inzunza, J.-A. Gustafsson, and R. Paus The Hair Follicle as an Estrogen Target and Source Endocr. Rev., October 1, 2006; 27(6): 677 - 706. [Abstract] [Full Text] [PDF]

				C.-Y. Cui, T. Hashimoto, S. I. Grivennikov, Y. Piao, S. A. Nedospasov, and D. Schlessinger Ectodysplasin regulates the lymphotoxin-beta pathway for hair differentiation PNAS, June 13, 2006; 103(24): 9142 - 9147. [Abstract] [Full Text] [PDF]

				A. A. Sharov, M. Fessing, R. Atoyan, T. Y. Sharova, C. Haskell-Luevano, L. Weiner, K. Funa, J. L. Brissette, B. A. Gilchrest, and V. A. Botchkarev Bone morphogenetic protein (BMP) signaling controls hair pigmentation by means of cross-talk with the melanocortin receptor-1 pathway PNAS, January 4, 2005; 102(1): 93 - 98. [Abstract] [Full Text] [PDF]

				U. Guha, L. Mecklenburg, P. Cowin, L. Kan, W. M. O'Guin, D. D'Vizio, R. G. Pestell, R. Paus, and J. A. Kessler Bone Morphogenetic Protein Signaling Regulates Postnatal Hair Follicle Differentiation and Cycling Am. J. Pathol., September 1, 2004; 165(3): 729 - 740. [Abstract] [Full Text] [PDF]