Giant congenital naevi are pigmented childhood lesions that frequently lead to melanoma, the most aggressive skin cancer. The mechanisms underlying this malignancy are largely unknown, and there are no effective therapies. Here we describe a mouse model for giant congenital naevi and show that naevi and melanoma prominently express Sox10, a transcription factor crucial for the formation of melanocytes from the neural crest. Strikingly, Sox10 haploinsufficiency counteracts Nras(Q61K)-driven congenital naevus and melanoma formation without affecting the physiological functions of neural crest derivatives in the skin. Moreover, Sox10 is also crucial for the maintenance of neoplastic cells in vivo. In human patients, virtually all congenital naevi and melanomas are SOX10 positive. Furthermore, SOX10 silencing in human melanoma cells suppresses neural crest stem cell properties, counteracts proliferation and cell survival, and completely abolishes in vivo tumour formation. Thus, SOX10 represents a promising target for the treatment of congenital naevi and melanoma in human patients.

Adult stem cells are essential for tissue renewal, regeneration, and repair, and their expansion in culture is of paramount importance for regenerative medicine. Using the whisker follicle of the rat as a model system, we demonstrate that (i) clonogenicity is an intrinsic property of the adult stem cells of the hair follicle; (ii) after cultivation for >140 doublings, these stem cells, transplanted to the dermo-epidermal junction of newborn mouse skin, form part or all of the developing follicles; (iii) the stem cells incorporated into follicles are multipotent, because they generate all of the lineages of the hair follicle and sebaceous gland; (iv) thousands of hair follicles can be generated from the progeny of a single cultivated stem cell; (v) cultured stem cells express the self-renewal genes Bmi1 and Zfp145; (vi) several stem cells participate in the formation of a single hair bulb; and (vii) there are many more stem cells in whisker follicles than could be anticipated from label-retaining experiments.skin ͉ transplantation

The thymus develops from the third pharyngeal pouch of the anterior gut and provides the necessary environment for thymopoiesis (the process by which thymocytes differentiate into mature T lymphocytes) and the establishment and maintenance of self-tolerance. It contains thymic epithelial cells (TECs) that form a complex three-dimensional network organized in cortical and medullary compartments, the organization of which is notably different from simple or stratified epithelia. TECs have an essential role in the generation of self-tolerant thymocytes through expression of the autoimmune regulator Aire, but the mechanisms involved in the specification and maintenance of TECs remain unclear. Despite the different embryological origins of thymus and skin (endodermal and ectodermal, respectively), some cells of the thymic medulla express stratified-epithelium markers, interpreted as promiscuous gene expression. Here we show that the thymus of the rat contains a population of clonogenic TECs that can be extensively cultured while conserving the capacity to integrate in a thymic epithelial network and to express major histocompatibility complex class II (MHC II) molecules and Aire. These cells can irreversibly adopt the fate of hair follicle multipotent stem cells when exposed to an inductive skin microenvironment; this change in fate is correlated with robust changes in gene expression. Hence, microenvironmental cues are sufficient here to re-direct epithelial cell fate, allowing crossing of primitive germ layer boundaries and an increase in potency.

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The branchial plume of the hydrothermal vent tubeworm Riftia pachyptila is the main organ by which this mouth- and gut-less tubeworm directly exchanges metabolites with its environment. We estimated the total branchial surface area per unit wet mass, termed the specific branchial surface area (SBSA), from planimetric measurements. Changes in the SBSA during the growth of the worm were inferred from 16 individuals ranging from 1 to 112 g wet mass. Riftia pachyptila has a mean SBSA of 22 cm2·g–1, the second highest among all aquatic animals, representing 9 times the surface area of the rest of the body. Three significantly different classes of SBSA could be distinguished, corresponding to small, medium-sized, and large individuals. The SBSA values for small and medium-sized R. pachyptila are twice that for large individuals. Negative growth allometry between the length of the branchial plume and that of the trunk may be correlated with this variation in SBSA, the plume growing faster than the trunk in the small and medium-sized groups. In large individuals the trunk length exceeds the plume length, inducing an increase in body mass that lowers the SBSA. However, a lower SBSA does not imply reduced metabolite diffusion through the plume of large tubeworms, since their longer free filaments bear more developed pinnules, which are probably the preferred pathway of metabolite diffusion, owing to a minimal transepithelial distance of 2 µm.

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The formation of hair follicles, a landmark of mammals, requires complex mesenchymal–epithelial interactions and it is commonly believed that embryonic epidermal cells are the only cells that can respond to hair follicle morphogenetic signals in vivo. Here, we demonstrate that epithelial stem cells of non-skin origin (e.g. that of cornea, oesophagus, vagina, bladder, prostate) that express the transcription factor Tp63, a master gene for the development of epidermis and its appendages, can respond to skin morphogenetic signals. When exposed to a newborn skin microenvironment, these cells express hair-follicle lineage markers and contribute to hair follicles, sebaceous glands and/or epidermis renewal. Our results demonstrate that lineage restriction is not immutable and support the notion that all Tp63-expressing epithelial stem cells, independently of their embryonic origin, have latent skin competence explaining why aberrant hair follicles or sebaceous glands are sometimes observed in non-skin tissues (e.g. in cornea, vagina or thymus).

T-cell development depends upon interactions between thymocytes and thymic epithelial cells (TECs). The engagement of delta-like 4 (DL4) on TECs by Notch1 expressed by blood-borne BM-derived precursors is essential for T-cell commitment in the adultthymus. In contrast to the adult, the earliest T-cell progenitors in the embryo originate in the fetal liver and migrate to the nonvascularized fetal thymus via chemokine signals. Within the fetal thymus, some T-cell precursors undergo programmed TCRγ and TCRδ rearrangement and selection, giving rise to unique γδ T cells. Despite these fundamental differences between fetal and adult T-cell lymphopoiesis, we show here that DL4-mediated Notch signaling is essential for the development of both αβ and γδ T-cell lineages in the embryo. Deletion of the DL4 gene in fetal TECs results in an early block in αβ T-cell development and a dramatic reduction of all γδ T-cell subsets in the fetal thymus. In contrast to the adult, no dramatic deviation of T-cell precursors to alternative fates was observed in the fetal thymus in the absence of Notch signaling. Taken together, our data reveal a common requirement for DL4-mediated Notch signaling in fetal and adult thymopoiesis.Keywords: Delta-like 4 · Fetal T-cell development · FoxN1Cre · Thymic epithelial cells Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionT cells differentiate in the thymus following sequential developmental steps that constantly require interaction with thymic epithelial cells (TECs), the major cell type of the thymic stroma. TECs are organized as a 3D network that facilitates thymocyte migration, and provide important thymopoietic factors such as Correspondence: Dr. Isabel Ferrero e-mail: Isabel.Ferrero@unil.ch Kit ligand, FLT3L, IL-7, CCL25, CXCL12, CCL19, and CCL21. Anatomically, the adult thymus is divided into cortex and medulla, each comprised of specialized TECs, cTECs (cortical epithelial cells) and mTECs (medullary epithelial cells), with different phenotype and function [1][2][3]. This epithelial compartmentalization of the adult thymus is essential for the correct development of T cells, and epithelial cells require specific interactions with developing thymocytes in order to maintain the cTEC versus mTEC specification. Such a mutual interdependency between thymocytes and TECs has been called "thymic crosstalk" [4].www.eji-journal.eu 2846 Isabel Ferrero et al. Eur. J. Immunol. 2013. 43: 2845-2853 In the adult, BM-derived common lymphoid precursors continuously seed the thymus from the bloodstream [5]. Inside the thymus, these precursors adopt a T-cell fate through a noncell autonomous process that strictly depends on Notch signaling mediated by interactions with cTECs. Notch signaling directs the lymphoid precursors towards a T-cell lineage differentiation program and blocks alternative lineage differentiation pathways [6][7][8][9].Fetal thymocyte development differs from the adult in two main aspects. First, fetal thymoc...