Plikus Maksim, Wang Wen Pin, Liu Jian, Wang Xia, Jiang Ting-Xin, Chuong Cheng-Ming
Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, California 90033, USA.
Am J Pathol. 2004 Mar;164(3):1099-114. doi: 10.1016/S0002-9440(10)63197-5.
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.
外胚层器官由角质形成细胞组成，这些角质形成细胞在诱导、形态发生、分化和再生阶段以不同方式组织。我们假设基本信号通路的失衡应以时空依赖的方式影响多个外胚层器官。我们制备了一种K14-Noggin转基因小鼠，以调节骨形态发生蛋白（BMP）活性并检验这一假设的程度。我们观察到皮肤表皮增厚、毛发密度增加、毛发类型改变、生长期重新进入加快以及复合触须毛囊形成。眼睑开口变小，以睑板腺为代价形成异位纤毛。在远端肢体，出现爪发育不全和色素沉着、指间蹼、脚垫减少以及汗腺向毛发的转分化。两性的外生殖器大小均增加，但它们仍具有生育能力。我们得出结论，BMP活性的调节可通过在诱导阶段起作用来影响外胚层器官的数量，通过在形态发生阶段起作用来影响大小和形状，通过在分化阶段起作用来改变表型，并通过在再生阶段起作用来促进新的生长。因此，在器官发生过程中，BMP拮抗剂可通过调节BMP活性水平以阶段依赖的方式产生一系列表型。本文还讨论了表型变异与病理变化之间的区别。
