Julie Lacombe

• Montreal Clinical Research Institute

Growth arrest–specific 6 (GAS6) is a secreted protein that acts as a ligand for TAM receptors (TYRO3, AXL, and MERTK). In humans, GAS6 circulating levels and genetic variations in GAS6 are associated with hyperglycemia and increased risk of type 2 diabetes. However, the mechanisms by which GAS6 influences glucose metabolism are not understood. Here...

Growth-arrest specific 6 (GAS6) is a secreted protein that acts as a ligand for TAM receptors (TYRO3, AXL and MERTK). In humans, GAS6 circulating levels and genetic variations in GAS6 are associated with hyperglycemia and increased risk of type 2 diabetes. However, the mechanisms by which GAS6 influences glucose metabolism are not understood. Here,...

Vitamin K is a micronutrient necessary for γ-carboxylation of glutamic acids. This post-translational modification occurs in the endoplasmic reticulum (ER) and affects secreted proteins. Recent clinical studies implicate vitamin K in the pathophysiology of diabetes, but the underlying molecular mechanism remains unknown. Here, we show that mouse β...

Patients with cystic fibrosis (CF) are at high risk of fat-soluble vitamin deficiencies, even with supplementation. The contribution of a suboptimal vitamin K status to respiratory and endocrine pathophysiology in CF has been inadequately characterized. This is a cross-sectional study in adult CF patients (≥18 years old) from the Montreal Cystic Fi...

Vitamin K (VK) is a micronutrient necessary for the γ-carboxylation of glutamic acids. This post- translational modification occurs in the endoplasmic reticulum (ER) and affects secreted proteins. Clinical studies have recently implicated VK in the pathophysiology of diabetes, but the underlying molecular mechanism remains unknown. Here, we show th...

Pou2af1 encodes for OCA‐B, a coactivator of OCT‐1/2 transcription factors, which plays a key role in B cell maturation. The function of OCA‐B has also been studied in T cells, where T cells from Pou2af1‐/‐ mice have impaired functions, such as cytokine production and T follicular helper (Tfh) differentiation. Arguably, some of these T cell phenotyp...

Osteocalcin (OCN) is an osteoblast-derived hormone with pleiotropic physiological functions. Like many peptide hormones, OCN is subjected to post-translational modifications (PTMs) which control its activity. Here, we uncover O -glycosylation as a novel PTM present on mouse OCN and occurring on a single serine (S8) independently of its carboxylatio...

PurposeBone may regulate glucose homeostasis via uncarboxylated bioactive osteocalcin (ucOCN). This study explored whether changes in ucOCN and bone remodeling are associated with change in glucose homeostasis after biliopancreatic diversion (BPD).Methods In this secondary exploratory analysis of a 1-year prospective observational study, 16 partici...

Osteocalcin (OCN) is an osteoblast-derived hormone with pleiotropic physiological functions. Like many peptide hormones, OCN is subjected to post-translational modifications (PTMs) which control its activity. Here, we uncover O -glycosylation as a novel PTM present on mouse OCN and occurring on a single serine (S8) independently of its carboxylatio...

Vitamin K is an essential nutrient involved in the regulation of blood clotting and tissue mineralization. Vitamin K oxidoreductase (VKORC1) converts vitamin K epoxide into reduced vitamin K, which acts as the co-factor for the γ-carboxylation of several proteins, including coagulation factors produced by the liver. VKORC1 is also the pharmacologic...

The current demographic shift toward an aging population has led to a robust increase in the prevalence of age-associated metabolic disorders. Interestingly, recent studies have demonstrated that the etiology of obesity-related insulin resistance developed upon aging differs from that induced by high-calorie diets. Whereas the role of adaptive immu...

Vertebrates possess 2 proteins with vitamin K oxidoreductase (VKOR) activity: VKORC1, whose vitamin K reduction supports vitamin K-dependent (VKD) protein carboxylation, and VKORC1-like 1 (VKORC1L1), whose function is unknown. VKD proteins include liver-derived coagulation factors, and hemorrhaging and lethality were previously observed in mice lac...

Osteocalcin (OCN) is an osteoblast-derived hormone that increases energy expenditure, insulin sensitivity, insulin secretion, and glucose tolerance. The cDNA sequence of OCN predicts that, like many other peptide hormones, OCN is first synthesized as a prohormone (pro-OCN). The importance of pro-OCN maturation in regulating OCN and the identity of...

Osteocalcin (OCN) is an osteoblast-derived hormone favoring glucose homeostasis, energy expenditure, male fertility, brain development, and cognition. Before being secreted by osteoblasts in the bone extracellular matrix, OCN is γ-carboxylated by the γ-carboxylase (GGCX) on three glutamic acid residues, a cellular process requiring reduction of vit...

Perivascular mesenchymal stem and progenitor cells (MSPCs) are critical for forming a healthy hematopoietic stem cell (HSC) niche. However, the interactions and influence of acute myelogenous leukemia (AML) stem cells with the microenvironment remain largely unexplored. We have unexpectedly found that neuropathy of the sympathetic nervous system (S...

Hematopoietic stem cells (HSC) reside in specific bone marrow niches comprised of perisinusoidal Nestin-GFP+ (Nes-GFP+) and leptin receptor (LepR)+ stromal cells which highly overlap with each other, as well as osteolineage and endothelial cells. These different cellular constituents regulate HSC maintenance and retention in the bone marrow (BM). R...

Osteocalcin is a hormone produced in bones by osteoblasts and regulating energy metabolism. While osteocalcin exists in two forms, γ-carboxylated and undercarboxylated only the latter appears to function as a hormone in vivo. It has been proposed recently that osteoclasts, the bone-resorbing cells, are responsible of decarboxylating, i.e. activatin...

In order to resorb the mineralized bone extracellular matrix, the osteoclast relies on the generation of a resorption lacuna characterized by the presence of specific proteases and a low pH. Hence, bone resorption by osteoclasts is highly dependent on lysosomes, the organelles specialized in intra- and extracellular material degradation. This is be...

Key Points Scl operates both downstream of Kit to control the survival of Kit+ multipotent and erythroid progenitors and upstream of Kit to determine Kit expression levels. Scl and Kit establish a positive feedback loop in hematopoietic progenitors.

The intermediate filament protein Nestin labels populations of stem/progenitor cells, including self-renewing mesenchymal stem cells (MSCs), a major constituent of the hematopoietic stem cell (HSC) niche. However, the intracellular location of Nestin prevents its use for prospective live cell isolation. Hence it is important to find surface markers...

The osteoblast-derived hormone osteocalcin promotes testosterone biosynthesis in the mouse testis by binding to GPRC6A in Leydig cells. Interestingly, Osteocalcin-deficient mice exhibit increased levels of luteinizing hormone (LH), a pituitary hormone that regulates sex steroid synthesis in the testes. These observations raise the question of wheth...

Bone resorption by osteoclasts requires a large number of lysosomes that release proteases in the resorption lacuna. Whether lysosomal biogenesis is a consequence of the action of transcriptional regulators of osteoclast differentiation or is under the control of a different and specific transcriptional pathway remains unknown. We show here, throug...

A critical step in the assembly of the neural circuits that control tetrapod locomotion is the specification of the lateral motor column (LMC), a diverse motor neuron population targeting limb musculature. Hox6 paralog group genes have been implicated as key determinants of LMC fate at forelimb levels of the spinal cord, through their ability to pr...

Hoxc9 is not derepressed at brachial levels in Hoxa6/Hoxc6 mutants. Serial sections at caudal brachial levels showing that Hoxc9 is normally restricted from FoxP1+ LMC neurons in Hoxc6 and Hoxa6/Hoxc6 mutants. At these levels Hoxc9 is normally expressed in neurons located dorsal to the LMC. Rostral to caudal is shown left to right. (PDF)

Analysis of tracer injections into the ulnar nerve in Hoxc6 mutants. (A) Summary of the position and distribution of the Pea3+ and Scip+ MN pools in the caudal half of the lateral motor column (cLMC). Relative positions of the pools in transverse sections are indicated for both control and Hoxc6 mutants. (B) Summary of the distribution of labeled M...

Analysis of MN columnar specification in Hoxa6/c6 mutants at e11.5. (A) Increase in the number of HMC neurons at rostral brachial levels in Hoxa6/Hoxc6 mutants at e11.5. Serial sections from rostral to caudal levels of the LMC are shown left to right. HMC neurons are identified by Hb9+Isl1/2 coexpression, indicated in cyan. (B, C) Normal expression...

Efficiency of LMC induction by Hox4–Hox8 proteins. (A) Examples of Hox electroporations in chick showing similar levels of protein expression to endogenous brachial levels. (B) Quantification of mean pixel intensities of Hox staining in n>40 nuclei of electroporated neurons at brachial and thoracic levels. (C) Quantification of the percentage of el...

Motor neuron pool defects in Hoxc6 mutants. (A–D) Additional examples of whole mount GFP staining showing defects in motor axon innervation of the cm muscle in Hoxc6 mutants at e12.5 and e13.5. (E) Loss of Pea3+ and retention of Scip+ motor neuron pools at e11.5 in Hox6 mutants. There is a marked decrease in the number of Pea3+ MNs at e11.5 in Hoxa...

Analysis of LMC specification in Hox6 mutants. (A) Total number of FoxP1+ LMC neurons in the brachial spinal cord of various Hox6 mutant allele combinations. (B) Levels of FoxP1 protein expression are reduced in rostral brachial regions in Hoxa6/Hoxc6 mutants. Levels were determined by measuring the pixel intensities of FoxP1 nuclear staining. (C,...

Analysis of LMC specification in Hox6 triple mutants. In mice lacking all three Hox6 genes (Hoxa6, Hoxb6, Hoxc6) LMC neurons are still generated in caudal brachial spinal cord, as assessed by FoxP1 and Raldh2 expression. In rostral brachial spinal cord, there is an additional loss in LMC neurons in triple mutants when compared to Hoxb6/c6 double mu...

505 Few markers have thus far been identified on native mesenchymal stem cells (MSCs), both in the mouse and human systems. Most markers cited in the literature are indeed based on expression analyses on heterogeneous cultured cell populations, which may not have self-renewal properties if rigorously tested by transplantation assays. Previous studi...

In the developing spinal cord, regional and combinatorial activities of Hox transcription factors are critical in controlling motor neuron fates along the rostrocaudal axis, exemplified by the precise pattern of limb innervation by more than fifty Hox-dependent motor pools. The mechanisms by which motor neuron diversity is constrained to limb level...

2520 Poster Board II-497 The life-long production of blood cells depends on the regenerative capacity of a rare bone marrow population, the hematopoietic stem cells (HSCs). In the adult, the majority of HSCs are quiescent while a large proportion of progenitors are more cycling. The state of quiescence in HSCs is reversible and these cells can be t...

The majority of long-term reconstituting hematopoietic stem cells (LT-HSCs) in the adult is in G(0), whereas a large proportion of progenitors are more cycling. We show here that the SCL/TAL1 transcription factor is highly expressed in LT-HSCs compared with short-term reconstituting HSCs and progenitors and that SCL negatively regulates the G(0)-G(...

SCL/TAL1 is a member of the basic helix-loop-helix family of transcription factors that also includes E2A and HEB. SCL is essential at the onset of hematopoiesis and activates transcription through heterodimerization with E2A. Both genes are expressed in long-term and short-term repopulating hematopoietic stem cells (HSCs) as assessed by expression...

The c-Kit tyrosine kinase receptor and the SCL/Tal1 (Stem Cell Leukemia) transcription factor are crucial to hematopoiesis and are co-expressed by hematopoietic progenitors. In the present study, we directly address the question whether SCL and c-Kit establish a code for the fate of multipotent progenitors in the adult. We therefore proceeded to lo...

The design of new antisense oligomers with improved binding affinity for targeted RNA, while still activating RNase H, is a major research area in medicinal chemistry. RNase H recognizes the RNA-DNA duplex and cleaves the complementary mRNA strand, providing the main mechanism by which antisense oligomers elicit their activities. It has been shown...

The Saccharomyces cerevisiae prohormone-processing enzyme Kex2p is biosynthesized as an inactive precursor extended by its N-terminal proregion. Here we show that deletion of the proregion renders Kex2p inactive both in vivo and in vitro. Absence of the proregion impaired glycosylation and stability and resulted in the retention of the enzyme in th...