Rôles des gènes Pitx dans le développement des membres postérieurs : régulation transcriptionnelle de Tbx4

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal

Optimizing Nervous System-Specific Gene Targeting with Cre Driver Lines: Prevalence of Germline Recombination and Influencing Factors.

The Cre-loxP system is invaluable for spatial and temporal control of gene knockout, knockin, and reporter expression in the mouse nervous system. However, we report varying probabilities of unexpected germline recombination in distinct Cre driver lines designed for nervous system-specific recombination. Selective maternal or paternal germline recombination is showcased with sample Cre lines. Collated data reveal germline recombination in over half of 64 commonly used Cre driver lines, in most cases with a parental sex bias related to Cre expression in sperm or oocytes. Slight differences among Cre driver lines utilizing common transcriptional control elements affect germline recombination rates. Specific target loci demonstrated differential recombination; thus, reporters are not reliable proxies for another locus of interest. Similar principles apply to other recombinase systems and other genetically targeted organisms. We hereby draw attention to the prevalence of germline recombination and provide guidelines to inform future research for the neuroscience and broader molecular genetics communities

Aspirine en prévention de la pré-éclampsie ?

Analyse de : "Villa PM, Kajantie E, Raïkkönen K, et al. Aspirin in the prevention of pre-eclampsia in high-risk women: a randomised placebo-controlled PREDO Trial and a meta-analysis of randomised trials. BJOG 2012;120:64-74." Question clinique : Cette étude de trop faible puissance ne permet pas de confirmer l’efficacité de l’administration d’aspirine dans la prévention de la pré-éclampsie chez des femmes à risque de pré-eclampsie et présentant des anomalies vélocimétriques au doppler des artères utérines. Conclusion Minerva : Quelle est l’efficacité, chez des femmes enceintes à haut risque et présentant des anomalies des artères utérines à l’écho-doppler, de l’administration d’aspirine débutée entre le 84 et le 97ème jour d’aménorrhée en termes de diminution du risque de pré-éclampsie

Apprivoiser les situations complexes

Depuis un an, le département de médecine générale de l’UCLouvain organise un cours pour les assistants généralistes intitulé « L’approche de la promotion de la santé appliquée à la médecine générale. Comment débloquer des situations complexes grâce à l’approche patient partenaire ? ». Derrière les mots, quels sont les enjeux de ce cours

Could the undergraduate French and Belgian training program explain the shortage of GPs in both countries?

Introduction: Shortage of manpower in GP/FM is a serious problem in Belgium and France. Despite the advertisement of some authorized voices, the evolution of the medical cursus in medicine has been oriented towards technology and specialties in the last 40 years and the low number of medical students attracted by the profession of GP is now a fact. Aim: In a attempt to explain this shortage, the author try to identify the similarities and dissimilarities between the undergraduate cursus in France and Belgium. Methods: • Exploring the training programs of the two structures one in Reims and one in Brussels (Univ of Louvain) • Participating to the vocational training sessions in both sites to meet the former undergraduate students • Conducting an inquiry with trainees in GP/FM in both sites about their choice of caree

A muscle-specific promoter directs Pitx3 gene expression in skeletal muscle cells

The Pitx homeobox transcription factor genes have been implicated in different developmental processes, including determination of hind limb identity for Pitx1, left-right asymmetry for Pitx2, and eye development and survival of midbrain dopaminergic neurons for Pitx3. Pitx1 and Pitx2 have partly redundant activities in craniofacial development, including in pituitary organogenesis, as indicated by their names. These genes also exhibit redundant activities in the control of hind limb bud growth. Recent studies have shown expression of the three Pitx genes in muscle, with Pitx3 being the most widely expressed in all skeletal muscles. We now report the identification of a muscle-specific promoter within the Pitx3 gene that is situated between the first exon for eye and brain expression and exon 2 that contains the initiator ATG codon. Sequences proximal to this muscle-specific exon 1 are essential and sufficient to confer muscle-specific expression in transgenic mice, they are responsive to myogenic basic helix-loop-helix regulatory factors, and they recruit these factors in vivo. In agreement with exclusive use of the muscle-specific promoter in aphakia mice that are deleted of the brain promoter, the trimethyl-lysine 4 histone H3 promoter signature shifts to this promoter in embryonic day 13 ak limb bud muscle cells. Myogenic basic helix-loop-helix regulatory factor activation of Pitx3 transcription may be part of a positive feedback loop contributing to establishment of the myogenic progra

DataSheet1_Loss of Neogenin alters branchial arch development and leads to craniofacial skeletal defects.pdf

The formation of complex structures, such as the craniofacial skeleton, requires precise and intricate two-way signalling between populations of cells of different embryonic origins. For example, the lower jaw, or mandible, arises from cranial neural crest cells (CNCCs) in the mandibular portion of the first branchial arch (mdBA1) of the embryo, and its development is regulated by signals from the ectoderm and cranial mesoderm (CM) within this structure. The molecular mechanisms underlying CM cell influence on CNCC development in the mdBA1 remain poorly defined. Herein we identified the receptor Neogenin as a key regulator of craniofacial development. We found that ablation of Neogenin expression via gene-targeting resulted in several craniofacial skeletal defects, including reduced size of the CNCC-derived mandible. Loss of Neogenin did not affect the formation of the mdBA1 CM core but resulted in altered Bmp4 and Fgf8 expression, increased apoptosis, and reduced osteoblast differentiation in the mdBA1 mesenchyme. Reduced BMP signalling in the mdBA1 of Neogenin mutant embryos was associated with alterations in the gene regulatory network, including decreased expression of transcription factors of the Hand, Msx, and Alx families, which play key roles in the patterning and outgrowth of the mdBA1. Tissue-specific Neogenin loss-of-function studies revealed that Neogenin expression in mesodermal cells contributes to mandible formation. Thus, our results identify Neogenin as a novel regulator of craniofacial skeletal formation and demonstrates it impinges on CNCC development via a non-cell autonomous mechanism.</p

The UBL domain of PLIC-1 regulates aggresome formation

Defects in protein folding and the proteasomal pathway have been linked with many neurodegenerative diseases. PLIC-1 (protein linking IAP to the cytoskeleton) is a ubiquitin-like protein that binds to the ubiquitin-interacting motif (UIM) of the proteasomal subunit S5a. Here, we show that PLIC-1 also binds to the UIM proteins ataxin 3—a deubiquitinating enzyme—HSJ1a—a co-chaperone—and EPS15 (epidermal growth factor substrate 15)—an endocytic protein. Using a polyglutamine (polyQ) disease model, we found that both endogenous PLIC-1 and EPS15 localize to perinuclear aggresomes, and that polyQ enhances their in vivo interaction. We show that knockdown of PLIC-1 and EPS15 by RNA interference reduces aggresome formation. In addition, PLIC-1(ΔUBL) functions as a dominant-negative mutant, blocking both polyQ transport to aggresomes and the association of EPS15 with dispersed aggregates. We also show that PLIC-1 is upregulated by arsenite-induced protein misfolding. These results indicate a role for PLIC-1 in the protein aggregation-stress pathway, and we propose a novel function for the ubiquitin-like (UBL) domain—by means of UBL–UIM interactions—in transport to aggresomes