Opposing roles for Hoxa2 and Hoxb2 in hindbrain oligodendrocyte patterning

Oligodendrocytes are the myelin-forming cells of the vertebrate CNS. Little is known about the molecular control of region-specific oligodendrocyte development. Here, we show that oligodendrogenesis in the mouse rostral hindbrain, which is organized in a metameric series of rhombomere-derived (rd) territories, follows a rhombomere-specific pattern, with extensive production of oligodendrocytes in the pontine territory (r4d) and delayed and reduced oligodendrocyte production in the prepontine region (r2d, r3d). We demonstrate that segmental organization of oligodendrocytes is controlled by Hoxgenes, namely Hoxa2 and Hoxb2. Specifically, Hoxa2 loss of function induced a dorsoventral enlargement of the Olig2/Nkx2.2-expressing oligodendrocyte progenitor domain, whereas conditional Hoxa2 overexpression in the Olig2(+) domain inhibited oligodendrogenesis throughout the brain. In contrast, Hoxb2 deletion resulted in a reduction of the pontine oligodendrogenic domain. Compound Hoxa2(-/-)/Hoxb2(-/-) mutant mice displayed the phenotype of Hoxb2(-/-) mutants in territories coexpressing Hoxa2 and Hoxb2 (rd3, rd4), indicating that Hoxb2 antagonizes Hoxa2 during rostral hindbrain oligodendrogenesis. This study provides the first in vivo evidence that Hox genes determine oligodendrocyte regional identity in the mammalian brain

Rôle des fractones, structure de la matrice extracellulaire, dans la niche neurogénique adulte

Chez l adulte, les cellules souches neurales (CSN) prolifèrent et se différencient dans des niches restreintes telles que la zone sous ventriculaire (ZSV). Au cœur de ces niches, facteurs de croissance et molécules de la matrice extracellulaire (MEC) sont impliqués dans le devenir de ces CSN. J ai eu pour objectif de caractériser une structure atypique de MEC, appelée fractone et d étudier son rôle dans la ZSE. J ai montré que les fractones étaient composées de molécules ubiquitaires de la MEC, que la formation de nouvelles cellules se faisait à proximité des fractones et que les fractones capturaient le facteur de croissance FGF-2 par un mécanisme de liaison aux chaines heparan sulfate. Par la suite, je me suis intéressé au rôle du Perlecan (HSPG présent dans les fractones) dans la niche neurogénique adulte. J ai mis en évidence que le Perlecan était nécessaire à la maintenance des CSN et à l action du FGF-2 sur les CSN pour leur passage d un stade quiescent vers un stade prolifératif. L ensemble de ces travaux suggère que les protéoglycanes constitutifs des fractones sont des molécules clés régulant la neurogenèse chez l adultePARIS-BIUSJ-Biologie recherche (751052107) / SudocSudocFranceF

Bacterial Lipopolysaccharides Exacerbate Neurogenic Heterotopic Ossification Development

International audienceNeurogenic heterotopic ossifications (NHO) are heterotopic bones that develop in periarticular muscles after severe central nervous system (CNS) injuries. Several retrospective studies have shown that NHO prevalence is higher in patients who suffer concomitant infections. However, it is unclear whether these infections directly contribute to NHO development or reflect the immunodepression observed in patients with CNS injury. Using our mouse model of NHO induced by spinal cord injury (SCI) between vertebrae T11 to T13, we demonstrate that lipopolysaccharides (LPS) from gram-negative bacteria exacerbate NHO development in a toll-like receptor-4 (TLR4)-dependent manner, signaling through the TIR-domain-containing adapter-inducing interferon-β (TRIF/TICAM1) adaptor rather than the myeloid differentiation primary response-88 (MYD88) adaptor. We find that T11 to T13 SCI did not significantly alter intestinal integrity nor cause intestinal bacteria translocation or endotoxemia, suggesting that NHO development is not driven by endotoxins from the gut in this model of SCI-induced NHO. Relevant to the human pathology, LPS increased expression of osteoblast markers in cultures of human fibro-adipogenic progenitors isolated from muscles surrounding NHO biopsies. In a case–control retrospective study in patients with traumatic brain injuries, infections with gram-negative Pseudomonas species were significantly associated with NHO development. Together these data suggest a functional association between gram-negative bacterial infections and NHO development and highlights infection management as a key consideration to avoid NHO development in patients