Biomedical subjects
Bruce A Morgan
Publications and source records attributed to Bruce A Morgan.
The ectodysplasin pathway in feather tract development.
The ectodysplasin pathway, comprising the ligand ectodysplasin, its receptor Edar and a dedicated death domain adaptor protein Edaradd, plays an important role in epidermal organ formation in mammals. Mutations in the genes encoding these proteins cause dysplasia or absence of teeth, sweat glands and hair follicles. However, the relative position of this pathway in the regulatory hierarchy directing follicle formation remains unclear. In this work, the chicken orthologs of Eda, Edar and Edaradd were cloned to exploit the temporal precision of the feather tract system in order to study the role of the ectodysplasin pathway. We find that these genes are expressed in a similar pattern during feather and hair development, with the notable difference that the ligand Eda, which is expressed in the epidermis of the mouse, is expressed in the dermis of the feather tract. Contrary to conclusions reached from the analysis of mutant mice, we find that localization of Edar expression to the nascent placode is coincident or subsequent to the local expression of other markers of placodal differentiation, and not an upstream event in tract patterning. Furthermore, forced expression of BMP and activated beta-catenin demonstrate that local expression of Edar is dictated by the interaction between these two pathways. These results suggest that activation of the ectodysplasin pathway may be permissive for activating signals to overcome signals that inhibit placode formation, but the function of this pathway in the specification of follicle initiation lies downstream of other patterning events.
Distinct stem cell populations regenerate the follicle and interfollicular epidermis.
The regeneration of the skin and its appendages is thought to occur by the regulated activation of a dedicated stem cell population. A population of cells in the bulge region of the hair follicle has been identified as the putative stem cell of both the follicle and the interfollicular epidermis. While this assertion is supported by a variety of surrogate assays, there has been no direct confirmation of the normal contribution of these cells to the regeneration of structures other than the cycling portion of the hair follicle. Here, we report lineage analysis revealing that the follicular epithelium is derived from cells in the epidermal placode that express Sonic hedgehog. This analysis also demonstrates that the stem cells resident in the follicular bulge that regenerate the follicle are neither the stem cells of the epidermis nor the source of the stem cells of the epidermis in the absence of trauma.
Wnt signaling through the beta-catenin pathway is sufficient to maintain, but not restore, anagen-phase characteristics of dermal papilla cells.
Dermal papilla cells of the hair follicle can be maintained in an active, hair-inducing state in vitro when cocultured with cells secreting Wnt3a. By inducing cultured dermal papilla cells to secrete Wnt themselves, we demonstrate that this activity is a direct effect of Wnt signaling to dermal papilla cells. We further demonstrate that the effects of Wnt3a are exerted through activation of the beta-catenin signal transduction pathway and do not require alternative Wnt transduction cascades. Once dermal papilla cells have lost hair-inducing properties in vitro, neither treatment with Wnt nor expression of a truncated and activating form of beta-catenin is sufficient to restore these properties to the cultured cells.
Expression and regulation of Groucho-related genes in the embryonic chicken feather bud.
The groucho-related gene (Grg) products modulate the transcriptional response to several extracellular signals, including the Wnts. In an effort to define the roles of Grgs in the morphogenesis of the feather bud, cDNAs encoding members of the Grg family were cloned from embryonic chick skin. In situ hybridization was used to localize transcripts for cGrg2, Grg3, Grg4, and Grg5 in embryos from day 6 through day 9. Expression of cGrg2, 3, and 5 is detected throughout the initial epidermal placode. As the buds mature, expression becomes limited to the posterior halves and eventually to the distal tip of the outgrowing bud. This pattern and the effects of forced activation of the bone morphogenetic protein and beta-catenin signal transduction pathways on Grg gene expression suggest that these genes act downstream of the early activation of the beta-catenin pathway that initiates placode formation. Induction of Grg genes by beta-catenin may serve as a negative feedback to modulate pathway activation while also altering the activity of other transduction pathways involved in bud patterning.
Opposing effects on TSC-22 expression by BMP and receptor tyrosine kinase signals in the developing feather tract.
TSC-22 (transforming growth factor-beta-stimulated clone 22) belongs to a family of leucine zipper transcription factors that includes sequences from invertebrates and vertebrates. The single Drosophila family member, encoded by the bunched gene, serves to integrate opposing bone morphogenic protein (BMP) and epidermal growth factor (EGF) signals during oogenesis. Similarly, mammalian TSC-22 expression is regulated by several families of secreted signaling molecules in cultured cells. Here, we show that chick TSC-22 is dynamically expressed in the condensing feather bud, as well as in many tissues of the chick embryo. BMP-2/4, previously shown to inhibit bud development, repress TSC-22 expression during feather bud formation in vivo. Noggin, a BMP antagonist, promotes TSC-22 expression. EGF, TGF-alpha, and fibroblast growth factor all promote both feather bud development and TSC-22 expression; each can promote ectopic feather buds that are regularly spaced between existing feather buds. Thus, TSC-22 is a candidate to integrate small imbalances in receptor tyrosine kinase and BMP signaling during feather tract development to generate stable and reproducible morphogenetic responses.