Predicting the spatiotemporal dynamics of hair follicle patterns in the developing mouse

Abstract

Reaction-diffusion models have been used as a paradigm for describing the de novo emergence of biological patterns such as stripes and spots. In many organisms, these initial patterns are typically refined and elaborated over the subsequent course of development. Here we study the formation of secondary hair follicle patterns in the skin of developing mouse embryos. We used the expression of sex-determining region Y box 2 to identify and distinguish the primary and secondary hair follicles and to infer the spatiotemporal dynamics of the follicle formation process. Quantitative analysis of the specific follicle patterns observed reveals a simple geometrical rule governing the formation of secondary follicles, and motivates an expansion-induction (EI) model in which new follicle formation is driven by the physical growth of the embryo. The EI model requires only one diffusible morphogen and provides quantitative, accurate predictions on the relative positions and timing of secondary follicle formation, using only the observed configuration of primary follicles as input. The same model accurately describes the positions of additional follicles that emerge from skin explants treated with an activator. Thus, the EI model provides a simple and robust mechanism for predicting secondary space-filling patterns in growing embryos.Turing pattern | growth and patterns | Voronoi analysis | inhibitory morphogen I n mouse skin development, well defined waves of induction during embryogenesis give rise to several major hair types. The first wave, starting around embryonic day 13 (E13), generates the future guard hair. This primary hair is the longest and is surrounded by Merkel cells (1, 2). The second wave (around E14.5-E16.5) generates two types of secondary hair: awls and auchenes. The third wave (around E17) generates the "Z" shape zigzag tertiary hair. During the formation of these hair types, smaller secondary follicles appear in the interstitial space of the larger primary follicles (1, 3). Unlike the feather buds in chick, which are organized in a highly ordered hexagonal array (4-6), mouse hair follicles are distributed in characteristic but less orderly space-filling patterns, the specifics of which have not been quantitatively characterized (Fig. 1A), and without which a quantitative assessment of pattern integrity in mutants cannot be made.Turing's analysis of the reaction-diffusion (RD) model, involving the diffusion of two types of morphogens ("activator" and "inhibitor") whose interaction regulates their own synthesis, has been regarded as a paradigm to explain the de novo emergence of approximately periodic patterns of epidermal appendages (reviewed in refs. 1, 3, and 7-11; SI Appendix, Note 1). The Turing class of RD models were postulated long ago to explain the initiation of skin appendage patterns (8,(12)(13)(14)(15), the secondary follicle patterns (16), the coat pattern (17), and skin pigmentation (7,18,19). Sick et al. (3) provided molecular evidence for regulators necessary in the formation of hair folli...

A multi-scale model for hair follicles reveals heterogeneous domains driving rapid spatiotemporal hair growth patterning

“…First anagen naturally follows the process of HF morphogenesis, which is known to be temporarily asynchronous, and to occur, at least in the dorsal skin, in three successive waves (reviewed in Clavel et al, 2012 ). Pattern-wise, development of HFs relies on reaction-diffusion ( Sick et al, 2006 ) and on space-filling expansion-induction mechanisms ( Cheng et al, 2014 ). Importantly, models for both mechanisms assume spatially synchronous HF morphogenesis.…”

Progenitors oppositely polarize WNT activators and inhibitors to orchestrate tissue development

“…In contrast to wild-type and/or Apc -/+ skin, where waves of LEF1+ placodes were patterned equidistantly in hexagonal arrays (Zhou et al 1995;Cheng et al 2014), hair follicle patterning was severely perturbed upon mosaic, autonomous over-stabilization of β-catenin ( Figure 1C -E). While immunostaining revealed intense nuclear β-catenin as well as nuclear LEF1, Apc-null clusters were of random sizes and organization and the clusters never developed into bona fide hair buds.…”

Ppp2r2a Knockout Mice Reveal That Protein Phosphatase 2A Regulatory Subunit, PP2A-B55α, Is an Essential Regulator of Neuronal and Epidermal Embryonic Development

“…cell orientation, and a complete lack of an epidermal layer in some segments (Figure 4A, black arrowhead). Furthermore, they showed no emerging hair follicles -a hallmark feature of normal epidermis at E14.5 (Mann, 1962;Hardy, 1992;Cheng et al, 2014).…”