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L’étude de l’hématopoïèse humaine a longtemps été limitée par l’accès aux prélèvements primaires de moelle osseuse. Afin de s’affranchir de cette contrainte, une approche originale de modélisation chez la souris immunodéficiente a été développée dans notre laboratoire. L’analyse de l’ensemble des populations cellulaires humaines générées dans la moelle osseuse des animaux greffés a permis d’établir une nouvelle cartographie de l’hématopoïèse humaine. Nous montrons que, contrairement aux prédictions du modèle canonique de l’hématopoïèse, la lymphopoïèse humaine présente une organisation bipartite, articulée autour de l’existence de deux familles de progéniteurs lymphoïdes identifiées par l’expression différentielle du récepteur de l’interleukine 7 (CD127). Outre leurs différences phénotypiques, les progéniteurs lymphoïdes CD127- et CD127+ se distinguent par leurs capacités de différenciation, leur dépendance vis-à-vis de facteurs de croissance, leurs modalités de restriction de potentiel, ainsi que par leurs signatures transcriptionnelles.

Chimpanzees (Pan troglodytes) and bonobos (P. paniscus) are our closest living relatives, with the human lineage diverging from the Pan lineage only around five to seven Mya, but possibly as early as eight Mya.1-2 Chimpanzees and bonobos even share genetic similarities with humans that they do not share with each other.2 Given their close genetic relationship to humans, both Pan species represent crucial living models for reconstructing our last common ancestor (LCA) and identifying uniquely human features. Comparing the similarities and differences of the two Pan is thus essential for constructing balanced models of human evolution.3.

The primary testis-determining function is exerted by a gene in the sex-determining region of the human Y chromosome. This gene is termed the sex-determining factor or TDF. A zinc finger gene, ZFY, residing in this region has been cloned and characterized. It is a candidate for TDF. A challenge to future molecular research is to clarify the function of a zinc finger gene on the X chromosome, ZFX, that shows high structural similarity to ZFY. Furthermore, the existence of other genes involved in sex determination is likely but so far unproven. Sex reversal leading to testes in apparently XX individuals (XX males) is most often due to the presence of TDF on the paternally derived X chromosome. The abnormality arises during meiosis in the father when an abnormal exchange leads to the transfer onto the X of the entire pseudoautosomal region plus a portion of the Y chromosome-specific region including TDF from the Y. An XX male resulting from such an exchange is described. 10-20% of XX males do not have Y DNA. Two major mechanisms to explain such Y(-) XX males are discussed. First, several published pedigrees show clear-cut dominant autosomal or X chromosomal inheritance of XX maleness. These patients are always Y(-) and usually have sexual ambiguity. This indicates the existence of other genes, obviously 'downstream' from TDF, that when mutated can trigger testis determination. Nothing concrete is presently known about these putative genes, but their phenotypic effect is slightly different from that of TDF. Second, mosaicism with a prevalent XX lineage and a hidden or scarce lineage containing a Y chromosome can explain some apparently Y(-) XX males. Two XX/XXY mosaic patients are described in detail. In one, only a combination of DNA hybridization and cytogenetic studies led to the discovery of the XXY cell line. In conclusion, XX sex reversal in man is caused by at least 3 mechanisms, viz. abnormal Y-X interchange, genes other than TDF, and mosaicism.