Although the hair shaft is derived from the progeny of keratinocyte stem cells in the follicular epithelium, the growth and differentiation of follicular keratinocytes is guided by a specialized mesenchymal population, the dermal papilla (DP), that is embedded in the hair bulb. Here we show that the number of DP cells in the follicle correlates with the size and shape of the hair produced in the mouse pelage. The same stem cell pool gives rise to hairs of different sizes or types in successive hair cycles, and this shift is accompanied by a corresponding change in DP cell number. Using a mouse model that allows selective ablation of DP cells in vivo, we show that DP cell number dictates the size and shape of the hair. Furthermore, we confirm the hypothesis that the DP plays a crucial role in activating stem cells to initiate the formation of a new hair shaft. When DP cell number falls below a critical threshold, hair follicles with a normal keratinocyte compartment fail to generate new hairs. However, neighbouring follicles with a few more DP cells can re-enter the growth phase, and those that do exploit an intrinsic mechanism to restore both DP cell number and normal hair growth. These results demonstrate that the mesenchymal niche directs stem and progenitor cell behaviour to initiate regeneration and specify hair morphology. Degeneration of the DP population in mice leads to the types of hair thinning and loss observed during human aging, and the results reported here suggest novel approaches to reversing hair loss.

Tropomyosin (Tm) is an ␣-helical coiled-coil that controls muscle contraction by sterically regulating the myosin-actin interaction. Tm moves between three states on F-actin as either a uniform or a non-uniform semi-flexible rod. Tm is stabilized by hydrophobic residues in the "a" and "d" positions of the heptad repeat. The highly conserved Asp-137 is unusual in that it introduces a negative charge on each chain in a position typically occupied by hydrophobic residues. The occurrence of two charged residues in the hydrophobic region is expected to destabilize the region and impart flexibility. To determine whether this region is unstable, we have substituted hydrophobic Leu for Asp-137 and studied changes in Tm susceptibility to limited proteolysis by trypsin and changes in regulation. We found that native and Tm controls that contain Asp-137 were readily cleaved at Arg-133 with t1 ⁄ 2 of 5 min. In contrast, the Leu-137 mutant was not cleaved under the same conditions. Actin stabilized Tm, causing a 10-fold reduction in the rate of cleavage at Arg-133. The actin-myosin subfragment S1 ATPase activity was greater for the Leu mutant compared with controls in the absence of troponin and in the presence of troponin and Ca 2؉ . We conclude that the highly conserved Asp-137 destabilizes the middle of Tm, resulting in a more flexible region that is important for the cooperative activation of the thin filament by myosin. We thus have shown a link between the dynamic properties of Tm and its function.Tropomyosin (Tm) 3 is a coiled-coil ␣-helix whose isoforms function in several ways when bound to F-actin. In skeletal and cardiac muscle, Tm controls contraction by regulating the binding of myosin to actin in conjunction with troponin (Tn) and Ca 2ϩ (1). Tm is also involved in the myosin-induced cooperative activation of the thin filament (2). In smooth muscle, Tm is involved in the cooperative activation of contraction by phosphorylated myosin (3). Non-muscle Tm stabilizes actin filaments and modulates the binding of other proteins (4). Equilibria between three thin filament states, B (blocked), C (closed or Ca 2ϩ -induced), O or M (open or myosin-induced), are involved in the regulation of muscle contraction (5). Ca 2ϩ binding to Tn facilitates the initial binding of myosin heads in the first step. In the second step, myosin heads cooperatively facilitate the movement of Tm into the O-state to allow isomerization of the heads and the generation of force. There are several single site Tm mutations that are involved in familial hypertrophic cardiomyopathy (6 -10) that increase the Ca 2ϩ sensitivity, indicating a shift into the B-state. However, the link between these mutations and the functional changes associated with familial hypertrophic cardiomyopathy is unknown.Coiled-coils are primarily stabilized by inter-helical hydrophobic interactions in positions a and d in the 7-residue pseudo repeat, a-to-g. Residues at a-and d-positions consist mainly of Leu, Ala, Leu, Val, Tyr, and Met. At position 137 in both ␣-and ␤-Tm ther...

The switch between black and yellow pigment is mediated by the interaction between Melanocortin receptor 1 (Mc1r) and its antagonist Agouti, but the genetic and developmental mechanisms that modify this interaction to obtain different coat color in distinct environments are poorly understood. Here, the role of Wnt/β-catenin signaling in the regulation of pigment-type switching was studied. Loss and gain of function of β-catenin in the dermal papilla (DP) of the hair follicle results in yellow and black animals, respectively. β-Catenin activity in the DP suppresses Agouti expression and activates Corin, a negative regulator of Agouti activity. In addition, β-catenin activity in the DP regulates melanocyte activity by a mechanism that is independent of both Agouti and Corin. The coordinate and inverse regulation of Agouti and Corin renders pelage pigmentation sensitive to changes in β-catenin activity in the DP that do not alter pelage structure. As a result, the signals that specify two biologically distinct quantitative traits are partially uncoupled despite their common regulation by the β-catenin pathway in the same cells.pheomelanin | eumelanin