Laboratory of Cutaneous Development

Overview

We study the mechanisms by which the naïve cells of the embryonic epidermis are assigned to different fates, whether that be the choice between epidermis or appendage (hair follicles and sweat glands), or the different variations of that fate on different regions of the body. Initial work in the lab fused classical embryology and retroiviral-mediated manipulation of gene expression to study feather and scale development in the chick embryo. We characterized the inductive signaling, both within the planer of the epidermis and between the epidermis and the mesenchyme and found it was also conserved, with minor modifications to accommodate the differences in determinate vs. indeterminate patterning, in hair follicle formation on the mouse. After the initial fate decision of hair follicle vs epidermis is made, a specialized inductive mesenchymal population, the dermal papilla, directs the differentiation of this rudiment into a Hair follicle and guides the elaboration of hair shafts of distinctive size shape and pigmentation. How this works remains an area of focus in the lab. Other active areas of research ask how this basic inductive signaling is modified for more distinctive outcomes such as the fate choice to become an eccrine gland vs a hair follicle, and how the ability to respond to these inductive signals is altered by prior experience as the organisms develops and matures.

Research Projects

How the dermal papilla specifies the size and shape of the hair and the cycling of the hair follicle

While the virus mediated gene expression system was well suited to probing these early patterning questions, it is ill-suited to dissecting the interactions between differentiated cell types in the developing organ. To expand our understanding of the genetic regulation of organogenesis and regeneration, I moved to the mouse where techniques for precise targeting of gene expression in differentiated cell populations are available. The field of epithelial stem cells was already densely populated, but we contributed lineage analysis of “stem cell” behaviors in vivo that substantially revised the prevailing models derived from indirect methods. Although the bulk of the hair follicle is formed and reformed by epithelial cells, a specialized dermal component directs the activity of these cells and the epithelial-mesenchymal interactions that drive budding morphogenesis in the limb are recapitulated here. My lab developed the tools to manipulate gene expression in this population in the mouse and continue to focus in the role of gene activity in DP cells to initiate regeneration and specify the morphology of the hair shaft.

1. Levy, V., Lindon, C., Harfe, B., and Morgan, B.A. Distinct stem cell populations regenerate the follicle and interfollicular epidermis. 2005; Dev. Cell 9(6) 855-861. PMID: 16326396
2. Kishimoto J, Burgeson R, Morgan BA. Wnt signaling maintains the hair inducing activity of the dermal papilla. Genes & Dev. 2000; 14:1181-1185. PMID: 10817753
3. Enshell-Seijffers, D. Lindon, C. Kashiwagi, M. and Morgan BA. ß-catenin activation in the dermal papilla directs morphogenesis of hair. 2010 Developmental Cell, 18, 633-642. PMCID: PMC2893731.
4. Chi W, Wu,E., Morgan BA. (2013). Dermal papilla cell number specifies hair size, shape and cycling and reduction in dermal papilla cell number causes follicular decline. (2013) Development 140, 1676-1683. PMCID: PMC3621486.

Cutaneous appendage fate choice : Hair follicles vs. Eccrine glands

Hair follicles are one of several cutaneous appendages that share overlapping genetic hierarchies that drive their development. We study the development of eccrine sweat glands to understand how appendage identity is specified. Candidate loci identified by comparative and quantitative genomics approaches are functionally evaluated in animal and in vitro models. This work identified En1 as a critical regulator of appendage identity capable of converting placodes in the interfootpad region of the mouse from a hair follicle to an eccrine gland fate.

1. Yana G. Kamberov*, Sijia Wang *, Jingze Tan, Pascale Gerbault, Abigail Wark, Longzhi Tan, Yajun Yang, Shilin Li, Kun Tang, Hua Chen, Adam Powell Yuval Itan, Dorian Q. Fuller, Jason Lohmueller, Junhao Mao, Mark G. Thomas, Li Jin, Daniel E. Lieberman, Clifford J. Tabin, Bruce A. Morgan°, Pardis C. Sabeti°. Modeling recent human evolution in mice by expression of a selected EDAR variant. (2013) Cell 152(4):691-702. PMCID: PMC3575602.
2. Kamberov , Y., Karlsson, E., Kamberova, G., Lieberman, D., Sabeti, P., Morgan, B.A*., Tabin, C*. A Genetic Basis of Variation in Eccrine Sweat Gland and Hair Follicle Density. (2015) PNAS USA,
   112(32):9932-7. PMCID: PMC4538659.

Epigenetic memory in the epidermis

Inductive signaling from the dermis is important for specifying particular types of skin, such as the specialized thickened skin of your palms and soles. However, once specified, the capacity of the epidermis to change fate is reduced, although not eliminated. One set of projects probes the ongoing requirements for inductive signaling to maintain regional skin types and how both the capacity to respond to different signals and the ability to maintain distinctive characters in their absence is encoded in the genome of epidermal stem cells at the epigenetic level.
An analogous phenomena is the “memory” of prior inflammation that is encoded in the epigenome of epidermal stem cells. During an episode of inflammation, tens of thousands of regulatory loci become accessible as a gene expression response to an exogenous challenge is mounted. When the challenge is dealt with, the skin returns to a homeostatic state and the majority of these regulatory loci return to their pre-inflammation configurations. However, several thousand regulatory remain in an altered chromatin state and are thought to poise their associated genes for more rapid response to subsequent challenge. We use this convenient system to study epigenetic memory in keratinocytes and probe its functional significance and mechanisms and how it is propagated over time as the stem cell population changes with age.
The approaches are similar to those described in our collaborative work on the epigenetics of lineage specification in the hematopoietic system.

1. Hu Y, Salgado Figueroa D, Zhang Z, Veselits M, Bhattacharyya S, Kashiwagi M, Clark MR, Morgan BA, Ay F, Georgopoulos
   K. Lineage-specific 3D genome organization is assembled at multiple scales by IKAROS. Cell. 2023 Nov 22;186(24):5269-
   5289.e22. PubMed Central PMCID: PMC10895928.
2. Shibata S, Kashiwagi M, Morgan BA, Georgopoulos K. Functional interactions between Mi-2β and AP1 complexes control
   response and recovery from skin barrier disruption. J Exp Med. 2020 Mar 2;217(3) PubMed Central PMCID: PMC7062528.

Publications

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