Clonal lineage information is fundamental in revealing cell fate choices. Using genetic single-cell labeling in utero, we investigated lineage segregations during anteroposterior axis formation in mouse. We show that while endoderm and surface ectoderm segregate during gastrulation, neural ectoderm and mesoderm share a common progenitor persisting through all stages of axis elongation. These data challenge the paradigm that the three germ layers, formed by gastrulation, constitute the primary branchpoints in differentiation of the pluripotent epiblast toward tissue-specific precursors. Bipotent neuromesodermal progenitors show self-renewing characteristics and may represent the cellular substrate coupling sustained axial elongation and coordinated differentiation of these tissues. These findings have important implications for the interpretation of the phenotypic defects of several mouse mutants and the directed differentiation of embryonic stem (ES) cells in vitro.

The WHIM syndrome is a rare immunodeficiency disorder characterized by warts, hypogammaglobulinemia, infections, and myelokathexis. Dominant heterozygous mutations of the gene encoding CXCR4, a G-protein-coupled receptor with a unique ligand, CXCL12, have been associated with this pathology. We studied patients belonging to 3 different pedigrees. Two siblings inherited a CXCR4 mutation encoding a novel C-terminally truncated receptor. Two unrelated patients were found to bear a wild-type CXCR4 open reading frame. Circulating lymphocytes and neutrophils from all patients displayed similar functional alterations of CXCR4-mediated responses featured by a marked enhancement of G-protein-dependent responses. This phenomenon relies on the refractoriness of CXCR4 to be both desensitized and internalized in response to CXCL12. Therefore, the aberrant dysfunction of the CXCR4-mediated signaling constitutes a common biologic trait of WHIM syndromes with different causative genetic anomalies. Responses to other chemokines, namely CCL4, CCL5, and CCL21, were preserved, suggesting that, in clinical forms associated with a wild-type CXCR4 open reading frame, the genetic anomaly might target an effector with some degree of selectivity for the CXCL12/ CXCR4 axis. We propose that the sus- IntroductionThe CXC chemokine stromal cell-derived factor 1 (SDF-1/ CXCL12) 1,2 is the sole natural ligand for CXCR4, 3,4 a broadly expressed G-protein-coupled receptor (GPCR). 5 The unique, nonpromiscuous interaction between CXCL12 and CXCR4 is critically involved in the organogenesis of a number of phylogenetically distant animal species. [6][7][8][9][10][11] In addition, B-cell lymphopoiesis and bone marrow (BM) myelopoiesis are regulated by the CXCL12/ CXCR4 axis during embryogenesis. [12][13][14] In postnatal life, the CXCL12/CXCR4 couple controls the BM homing of CD34 ϩ cells and lymphocyte trafficking. [15][16][17][18] Besides the regulation of homeostatic processes, CXCR4 has been implicated in the development of infectious 3,19 and inflammatory diseases as well as tumor metastasis. [20][21][22][23] Recently, inherited heterozygous autosomal dominant mutations of the CXCR4 gene, which result in the truncation of the carboxyl-terminus (C-tail) of the receptor, were found to be associated with the WHIM syndrome. 24 This rare immunodeficiency disease is characterized by disseminated human papillomavirus (HPV)-induced warts, hypogammaglobulinemia, recurrent bacterial infections, and myelokathexis, a form of neutropenia associated with abnormal retention of mature neutrophils in the BM. [25][26][27] Patients with WHIM also exhibit a marked T-cell lymphopenia. The disorder is clinically and genetically heterogeneous, 28 since hypogammaglobulinemia and verrucosis were absent in some cases, 29 and individuals with isolated myelokathexis were found to be wild type for the CXCR4 gene. 24 However, the altered mechanism accounting for the pathogenesis of the WHIM syndrome not associated to CXCR4 mutations remains unknown. Here, we provide original...

When and how cells form and pattern the myocardium is a central issue for heart morphogenesis. Many genes are differentially expressed and function in subsets of myocardial cells. However, the lineage relationships between these cells remain poorly understood. To examine this, we have adopted a retrospective approach in the mouse embryo, based on the use of the laacZ reporter gene, targeted to the alpha-cardiac actin locus. This clonal analysis demonstrates the existence of two lineages that segregate early from a common precursor. The primitive left ventricle and the presumptive outflow tract are derived exclusively from a single lineage. Unexpectedly, all other regions of the heart, including the primitive atria, are colonized by both lineages. These results are not consistent with the prespecification of the cardiac tube as a segmented structure. They are discussed in the context of different heart fields and of the evolution of the heart.

Contact dermatitis is a common inflammatory skin disease in industrialized countries with a great socioeconomic impact. It is one of the most common occupational diseases (1, 2). As the outermost barrier of the human body, the skin is the first to encounter chemical and physical factors from the environment. Two main types of contact dermatitis may be distinguished, according to the pathophysiological mechanisms involved: (i) irritant contact dermatitis is the expression of the proinflammatory and toxic effects of xenobiotics able to activate the skinÕs innate immune system and (ii) allergic contact dermatitis (ACD) requires the activation of antigen (Ag)-specific acquired immunity, leading to the development of effector T cells (T EFF ), which mediate the skin inflammation. ACD occurs at the site of contact with an allergen called a hapten, in sensitized individuals, and it is characterized by redness, papules and vesicles, followed by scaling and dry skin. Systemic administration of hapten to sensitized patients may possibly result in systemic ACD (3, 4). HaptensThe origin and nature of the compounds able to induce an ACD reaction are very diverse, and comprise a limited number of strong contact sensitizers used in animal models of ACD and thousands of weak haptens responsible for human ACD (5, 6). Contact allergens are low molecular weight chemicals that behave as haptens as they are not immunogenic by themselves and need to bind to epidermal proteins to generate new antigenic determinants. Most haptens bear lipophilic residues, which enable them to cross through the corneal barrier, and electrophilic residues, which account for covalent bonds to the nucleophilic residues of cutaneous proteins (7).Allergic contact dermatitis (ACD), one of the commonest occupational diseases, is a T-cell-mediated skin inflammation caused by repeated skin exposure to contact allergens, i.e. nonprotein chemicals called haptens. Allergic contact dermatitis, also referred to as contact hypersensitivity, is mediated by CD8+ T cells, which are primed in lymphoid organs during the sensitization phase and are recruited in the skin upon re-exposure to the hapten. Subsets of CD4+ T cells endowed with suppressive activity are responsible for both the downregulation of eczema in allergic patients and the prevention of priming to haptens in nonallergic individuals. Therefore, ACD should be considered as a breakdown of the skin immune tolerance to haptens. Recent advances in the pathophysiology of ACD have demonstrated the important role of skin innate immunity in the sensitization process and have revisited the dogma that Langerhans cells are mandatory for CD8+ T-cell priming. They have also introduced mast cells as a pivotal actor in the magnitude of the inflammatory reaction. Finally, the most recent studies address the nature, the mode and the site of action of the regulatory T cells that control the skin inflammation with the aim of developing new strategies of tolerance induction in allergic patients.