Establishment and Maintenance of Hair Follicle Size

We have a fair understanding of how each of our organs begins development before birth, but know much less regarding how the growth of each organ is controlled to give us a correctly proportioned anatomy. This project will examine the events that determine the size of our hair follicles, one of our most numerous organs. Mammals carry hair follicles of different sizes across almost all of the skin. The areas with large follicles, such as the scalp, produce thick, visible hairs. The areas with small follicles, such as the forehead, produce tiny, almost invisible hairs. The idea behind this work is that hair follicle size differences are set in the embryonic skin in a very dynamic cell signalling process. This signalling process is temporary, but leaves a lasting impact on the skin by converting some skin cells into the root of the hair follicle. The number of cells converted to hair root is based on the relative amounts of conflicting signals present in the embryonic skin, and once these temporary signals have faded the job of controlling hair size is taken on permanently by the cells at the very base of the follicle. This project will test each step of this process using mouse skin from different parts of the body. As hair follicles develop in a manner similar to that of internal organs, such as the gut, lung and kidney, the results will help us to understand how organ size in general is controlled. Also, understanding the control of hair follicle size will enable us to control this in the future, for example increasing follicle size in humans with baldness and engineering sheep that produce more, and better quality, wool.

Despite being one of the most apparent features of an organ or an organism, the mechanisms of size determination are poorly understood indeed. Studies of visceral organs indicate that multiple size determination mechanisms can operate. For example, the size of the pancreas depends on the number of progenitor cells that constitute its embryonic rudiment, while the liver appears to undergo a constant sensing of size, such that partial ablation or induction of liver overgrowth is corrected when the experimental influence is removed. In this project the mechanisms governing the size determination of a mini-organ, the hair follicle, will be examined. Hair follicles are a good model for organ development as they are numerous, not essential for organism viability, complex at the cellular level, and display dramatically different sizes on different regions of the skin. In addition, hair follicles develop as a result of extensive epithelial-mesenchymal interactions, similar to the tissue interactions that guide the development of the lung, kidney, gut and teeth. Our preliminary studies have led us to formulate a size determining hypothesis that relies on embryonic patterning mechanisms to establish organ rudiment size, followed by maintenance of mature organ size through a shift in inductive potential. This shift in the basis of follicle size determination involves an inductive event that templates the embryonic organ rudiment characteristics onto a stable dermal cell population that persists through adult life. This dermal population then maintains follicle size through lifelong cycles of regression and regeneration. The work will test each prediction of the hypothesis and address the molecular mechanisms of size determination. Alternative sizing hypotheses will be considered and tested experimentally.

This project aims to understand the molecular and cellular mechanisms of organ size determination. The immediate impact will chiefly be upon the academic beneficiaries and the general public, with future impacts related to economic competitiveness. The general public are interested in hair characteristics, which are a uniquely defining feature of many animals, such as sheep or hedgehogs. In addition, the obvious differences in hair fibre size across different parts of the human skin, and the changes associated with ageing, also contribute to the interest in this subject. The impact of this project upon the public will thus be enhanced by the 'real-world' nature of the organ studied. The striking images produced in studies of spatial patterning make this area ideal for public engagement activities. In this regard the use of cultured skin tissues, rather than Protected Animals, where possible, will aid public engagement and acceptance. Academic beneficiaries will gain from insights into the very poorly understood process of organ size determination. The multiple steps of this process examined, and the novel hypothesis being tested, will be comparable to other organs that develop via epithelial-mesenchymal interaction. There will also be practical applications arising from this work that could be employed to modulate hair characteristics in species other than mice. Hair follicle size dictates hair fibre characteristics, particularly the thickness of hair fibres. In agriculture, the ability to modulate the spacing and size of hair follicles during development will allow the engineering of the fleece. The quality of wool is based on the fineness of its hair fibres. This project will reveal how hair follicle patterning can be altered to yield a high density of small hair follicles, or a low density of large ones, the former representing a means to improve wool characteristics. In humans, knowledge of the cell populations that dictate hair follicle size in adult skin will allow the design of approaches to increase or decrease this feature, thereby enabling stimulation or suppression of visible hair growth as a new means to treat hirsutism or baldness.