Mutations of the spastin gene (Sp) are responsible for the most frequent autosomal dominant form of spastic paraplegia, a disease characterized by the degeneration of corticospinal tracts. We show that a deletion in the mouse Sp gene, generating a premature stop codon, is responsible for progressive axonal degeneration, restricted to the central nervous system, leading to a late and mild motor defect. The degenerative process is characterized by focal axonal swellings, associated with abnormal accumulation of organelles and cytoskeletal components. In culture, mutant cortical neurons showed normal viability and neurite density. However, they develop neurite swellings associated with focal impairment of retrograde transport. These defects occur near the growth cone, in a region characterized by the transition between stable microtubules rich in detyrosinated alpha-tubulin and dynamic microtubules composed almost exclusively of tyrosinated alpha-tubulin. Here, we show that the Sp mutation has a major impact on neurite maintenance and transport both in vivo and in vitro. These results highlight the link between spastin and microtubule dynamics in axons, but not in other neuronal compartments. In addition, it is the first description of a human neurodegenerative disease which involves this specialized region of the axon.

The recent and rapid worldwide increase in non-communicable diseases challenges the assumption that genetic factors are the primary contributors to such diseases. A new concept of the 'developmental origins of health and disease' (DOHaD) is at stake and therefore requires a paradigm shift. Maternal obesity and malnutrition predispose offspring to develop metabolic syndrome, a vicious cycle leading to transmission to subsequent generation(s), with differences in response and susceptibility according to the sex of the individual. The placenta is a programming agent of adult health and disease. Adaptations of placental phenotype in response to maternal diet and metabolic status alter fetal nutrient supply. This implies important epigenetic changes that are, however, still poorly documented in DOHaD studies, particularly concerning overnutrition. The aim of this review is to discuss the emerging knowledge on the relationships between the effect of maternal nutrition or metabolic status on placental function and the risk of diseases later in life, with a specific focus on epigenetic mechanisms and sexual dimorphism. Explaining the sex-specific causal variables and how males versus females respond and adapt to environmental perturbations should help physicians and patients to anticipate disease susceptibility.KEY WORDS: DOHaD, Fetal programming, Placenta, Sex, Nutrition, Obesity, Maternal environment, Gestation Introduction: developmental origins of health and diseaseThe recent and rapid worldwide increase in non-communicable diseases (NCDs) challenges the assumption that genetic factors are the primary contributors to such diseases (McAllister et al., 2009). The 'developmental origins of health and disease' (DOHaD) paradigm states that the environment during the periconception, gestation and lactation periods shapes the developing individuals, leading, in the case of a deleterious environment, to a predisposition to adult-onset diseases. This theory was popularised by D. J. Barker in the early 1990s (Barker, 1990) but the question had already been raised in earlier studies. In the 1960s and 1970s, different experiments on diverse mammalian species (rat, mouse, guinea pig, pig, etc.) showed that a reduction of maternal calorie or protein intake during pregnancy and lactation affects the growth capacity and cognitive ability of the offspring (reviewed in Roeder and Chow, 1972;McCance, 1976). Later, this concept was extended to phenotype in general, with a strong implication for quantitative traits in agriculture. An increasing number of studies pointed to the fact that maternal environment in cattle was an important parameter to fully express the genetically highly selected potential of the animals (Wallace et al., 2010; Jammes et al., 2011;Tanghe et al., 2014).Male and female susceptibility to NCDs is well described. It appears that in the DOHaD context, the same environmental exposure may affect the long-term health of the offspring with a discrepancy between males and females in terms of the timing, onset ...

SUMMARY:Trophoblasts of the human placenta differentiate along two pathways to give either extravillous cytotrophoblasts (EVCT) with invasive properties and that are implicated in the implantation process, or villous cytotrophoblasts (VCT) that by cell fusion form multinucleated syncytiotrophoblasts. We report the first isolation and purification of these two cell types from the same chorionic villi of first trimester human placenta. We also studied their differentiation in vitro. Electron microscopy showed that in contrast to VCT, EVCT had no microvilli but contained large fibrinoid inclusions. EVCT cultures required a matrix to invade, and as previously established, VCT cultured on plastic dishes aggregated and fused to form syncytiotrophoblasts. These differentiation processes were characterized by a particular pattern of gene expression as assessed by real-time PCR and confirmed by immunocytochemical analysis of the corresponding proteins. EVCT cultured in vitro expressed high levels of HLA-G, c-erbB2, human placental lactogen, and very little human chorionic gonadotropin. Interestingly, TGF␤2 was a marker of EVCT in vitro and in situ. These data offer a new tool for cell biologists to study the molecular mechanisms involved in human placental development and its pathology. (Lab Invest 2001, 81:1199 -1211.