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McCann M.R.,University of Western Ontario | Tamplin O.J.,Childrens Hospital Boston | Rossant J.,Program in Developmental and Stem Cell Biology | Rossant J.,University of Toronto | Seguin C.A.,University of Western Ontario
DMM Disease Models and Mechanisms | Year: 2012

Back pain related to intervertebral disc degeneration is the most common musculoskeletal problem, with a lifetime prevalence of 82%. The lack of effective treatment for this widespread problem is directly related to our limited understanding of disc development, maintenance and degeneration. The aim of this study was to determine the developmental origins of nucleus pulposus cells within the intervertebral disc using a novel notochord-specific Cre mouse. To trace the fate of notochordal cells within the intervertebral disc, we derived a notochord-specific Cre mouse line by targeting the homeobox gene Noto. Expression of this gene is restricted to the node and the posterior notochord during gastrulation [embryonic day 7.5 (E7.5)-E12.5]. The Noto-cre mice were crossed with a conditional lacZ reporter for visualization of notochord fate in whole-mount embryos. We performed lineage-tracing experiments to examine the contribution of the notochord to spinal development from E12.5 through to skeletally mature mice (9 months). Fate mapping studies demonstrated that, following elongation and formation of the primitive axial skeleton, the notochord gives rise to the nucleus pulposus in fully formed intervertebral discs. Cellular localization of ?-galactosidase (encoded by lacZ) and cytokeratin-8 demonstrated that both notochordal cells and chondrocyte-like nucleus pulposus cells are derived from the embryonic notochord. These studies establish conclusively that notochordal cells act as embryonic precursors to all cells found within the nucleus pulposus of the mature intervertebral disc. This suggests that notochordal cells might serve as tissue-specific progenitor cells within the disc and establishes the Noto-cre mouse as a unique tool to interrogate the contribution of notochordal cells to both intervertebral disc development and disc degeneration. © 2012. Published by The Company of Biologists Ltd.

Scott I.C.,Program in Developmental and Stem Cell Biology | Scott I.C.,University of Toronto
Current Topics in Developmental Biology | Year: 2012

Development of the heart, like that of other organs, requires the specification of progenitor cell populations that will ultimately form the differentiated cell types of the functional organ. A relatively recent and exciting advance in cardiac research has been the identification of cardiovascular progenitor cells (CPCs), which have the potential to form the major cell types of the heart (cardiomyocytes, smooth muscle, and endothelium/endocardium). This suggests that a common progenitor is responsible for much of heart development and has spurred great interest in use of CPC-like cells for cardiac repair. In this review, CPC development is discussed, with a focus on early events prior to the initiation of cardiac gene expression. In particular, I discuss evidence that CPC fate is established during gastrulation, well before a time when heart development has typically been studied. Pathways regulating CPC specification are examined. The relationship between CPC specification and migration is further discussed. Finally, how CPCs may be related to efforts to promote cardiac development by approaches including reprogramming is discussed. © 2012 Elsevier Inc.

Gallagher D.,Program in Developmental and Stem Cell Biology
Cell stem cell | Year: 2013

The mechanisms that regulate the establishment of adult stem cell pools during normal and perturbed mammalian development are still largely unknown. Here, we asked whether a maternal cytokine surge, which occurs during human maternal infections and has been implicated in cognitive disorders, might have long-lasting consequences for neural stem cell pools in adult progeny. We show that transient, maternally administered interleukin-6 (IL-6) resulted in an expanded adult forebrain neural precursor pool and perturbed olfactory neurogenesis in offspring months after fetal exposure. This increase is likely the long-term consequence of acute hyperactivation of an endogenous autocrine/paracrine IL-6-dependent self-renewal pathway that normally regulates the number of forebrain neural precursors. These studies therefore identify an IL-6-dependent neural stem cell self-renewal pathway in vivo, and support a model in which transiently increased maternal cytokines can act through this pathway in offspring to deregulate neural precursor biology from embryogenesis throughout life. Copyright © 2013 Elsevier Inc. All rights reserved.

Blake J.,Program in Developmental and Stem Cell Biology | Blake J.,University of Toronto | Rosenblum N.D.,The Hospital for Sick Children | Rosenblum N.D.,University of Toronto
Seminars in Cell and Developmental Biology | Year: 2014

The human kidney is composed of an arborized network of collecting ducts, calyces and urinary pelvis that facilitate urine excretion and regulate urine composition. The renal collecting system is formed in utero, completed by the 34th week of gestation in humans, and dictates final nephron complement. The renal collecting system arises from the ureteric bud, a derivative of the intermediate-mesoderm derived nephric duct that responds to inductive signals from adjacent tissues via a process termed ureteric induction. The ureteric bud subsequently undergoes a series of iterative branching and remodeling events in a process called renal branching morphogenesis. Altered signaling that disrupts patterning of the nephric duct, ureteric induction, or renal branching morphogenesis leads to varied malformations of the renal collecting system collectively known as congenital anomalies of the kidney and urinary tract (CAKUT) and is the most frequently detected congenital renal aberration in infants. Here, we describe critical morphogenetic and cellular events that govern nephric duct specification, ureteric bud induction, renal branching morphogenesis, and cessation of renal branching morphogenesis. We also highlight salient molecular signaling pathways that govern these processes, and the investigative techniques used to interrogate them. © 2014 Elsevier Ltd.

Liu J.C.,Toronto General Research Institute | Egan S.E.,Program in Developmental and Stem Cell Biology | Zacksenhaus E.,Toronto General Research Institute
Oncotarget | Year: 2013

The high intra- and inter-tumor heterogeneity of many types of cancers, including breast cancer (BC), poses great challenge to development of subtype-specific prognosis. In BC, the classification of tumors as either ERa+ (Luminal A and Luminal B), HER2+ (ERa+ or ERa-) or triple-negative (TNBC)(Basal-like, claudin-low) guides both prognostication and therapy. Indeed, prognostic signatures for ERa+ BC are being incorporated into clinical use. However, these signatures distinguish between luminal A (low risk) and Luminal B (high risk) BC; signatures that identify low/ high risk patients with luminal B BC are yet to be developed. Likewise, no signature is in clinical use for HER2+ or TNBC. The major obstacles to development of robust signatures stem from diversity of BC, clonal evolution and heterogeneity within each subtype. We have recently generated a prognostic signature for HER2+:ERa- BC based on the identification of genes that were differentially expressed in a tumor-initiating cell (TIC)-enriched fraction versus non-TIC fraction from a mouse model of HER2+ BC (MMTV-Hers/Neu). Here we describe the rationale behind development of this prognosticator, and present new features of the signature, including elevated PI3K pathway activity and low TNFalpha and IFNgamma signaling in high-risk tumors. In addition, we address controversies in the field such as whether random gene expression signatures significantly associate with cancer outcome. Finally, we suggest a guideline for development of prognostic signatures and discuss future directions.

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