Distinct mechanisms underlie pattern formation in the skin and skin appendages

Abstract

Patterns form with the break of homogeneity and lead to the emergence of new structure or arrangement. There are different physiological and pathological mechanisms that lead to the formation of patterns. Here, we first introduce the basics of pattern formation and their possible biological basis. We then discuss different categories of skin patterns and their potential underlying molecular mechanisms. Some patterns, such as the lines of Blaschko and Naevus, are based on cell lineage and genetic mosaicism. Other patterns, such as regionally specific skin appendages, can be set by distinct combinatorial molecular codes, which in turn may be set by morphogenetic gradients. There are also some patterns, such as the arrangement of hair follicles (hair whorls) and fingerprints, which involve genetics as well as stochastic epigenetic events based on physiochemical principles. Many appendage primordia are laid out in developmental waves. In the adult, some patterns, such as those involving cycling hair follicles, may appear as traveling waves in mice. Since skin appendages can renew themselves in regeneration, their size and shape can still change in the adult via regulation by hormones and the environment. Some lesion patterns are based on pathological changes involving the above processes and can be used as diagnostic criteria in medicine. Understanding the different mechanisms that lead to patterns in the skin will help us appreciate their full significance in morphogenesis and medical research. Much remains to be learned about complex pattern formation, if we are to bridge the gap between molecular biology and organism phenotypes.

Fig. 1. Basics on pattern formation

A–E, schematic drawings showing basic patterns. F–T, possible mechanism that can lead to pattern changes. U–Z, additional factors that can influence biological pattern formatting due to the growth. Panel E is from Yue et al., 2005. Panel M is from Jiang et al., 2004. P U–X can represent trunk with midline on the top. There are three possible ways new cells can be added, which are indicated by the green color. Panel Y, Z indicate the changes of field shape which can represent the growth of limb bud, tail bud or feather bud. Please see text for further explanation.

Fig. 2. Patterns on avian skin and skin appendages and hierarchical morphogenesis

A) male an female pheasants do show regional specific skin appendages and sexual dimorphism. Also note the thick pigment stripes and dots in the tail feather. Prum and Williamsons (2002) proposed a reaction diffusion model for feather pigment patterning. B) Different developmental stages of skin appendage morphogenesis. Note the different types of skin appendages, including the schematic radially and bilaterally symmetric feathers. Modified from Wu et al., 2004.

Fig. 3. Temporal wave

A. Shh in situ hybridization of embryonic chicken skin. Midline is indicated by an arrow. Feather bud formation starts from the midline, and then lateral buds appear sequentially. From the lateral edge to the midline are regions of no feather primordia, feather placodes, short buds, long buds and feather filaments with branch formation. B. Beta catenin in situ hybridization. The feather field first homogenously expresses beta catenin at a moderate level in the morphogenetic zone. Then the periodically arranged buds emerge gradually expressing high levels of beta catenin, and the lateral inhibitory zone does not express beta catenin. From Widelitz et al., 2000.

Fig. 4. Morphogenetic gradient

Left column: an idealized radially symmetric feather. Right column: a bilaterally symmetric feather. A, E, The proximal follicle showed ordered compartments of stem cell (orange color), TA cell and differentiating cells (ramogenic zone) (Yue et al., 2005). In radially symmetric feathers, the ring is horizontal. In the bilaterally symmetric feathers, θ is tilted from zero to about 45°. The molecular gradient in the ramogenic zone is shown in shades of blue. B, C, In an open follicle preparation, the feather filament cylinder is opened to form a plane. In radially symmetric feathers, all new barb ridges form at the same time and in parallel. In bilaterally symmetric feathers, the tilting of the stem cell ring results in a discrepancy of maturation due to the fact that the TA cells have to travel (or are displaced) different distances before they reach the ramogenic zone (m1 and m2). In the anterior side, cells are more mature. The shift of cell positions is represented by vectors AB, AC and AD. D, According to this model, there should be a molecular gradient along the A–P axis. Indeed we found a Wnt 3a gradient. Flattening the gradient converted feathers from bilateral to radial symmetry (Yue et al., 2006).

Fig. 5. Traveling stripes

In the adult mouse, hair follicles go through regenerative cycling. They appear as black in the anagen. In this mutant nude mouse, hair filaments are lost in the telogen period and appear white. This helps us visualize the changing state of hair follicles which appear as traveling waves (after Suzuki et al., 2003; Plikus and Chuong, 2004). Arrows describe the direction of wave propagation.

Fig. 6. Genetic mosaicism on the skin

A. Line of Blaschko. Through x chromosome inactivation, lineage of epithelia cells can be seen to be distributed in lines horizontal to the body A–P axis. Several examples of chekerboard or patch patterns on human skin are seen in several human diseases (Happle, 1995, 2004). After Happle’s viewpoint 2 in Chuong et al., 2006. B, Equivalent line of Blaschko in embryonic chicken. Embryos are injected with non-replicative virus carrying beta-galactosidase. C, line drawing of B. D, Different cell lineages are represented by different colors. Analyses show that individual feather buds or individual barb ridges are made of cells from different lineages, not from single lineage. Therefore, the local environment at the time of feather morphogenesis is more important than lineage. B–D, from Chuong et al., 1998.