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Abstracts of papers presented at the 23rd Genetics Society's Mammalian Genetics and Development Workshop held at the Institute of Child Health, University College London on 22nd November 2012

NICHOLAS D. E. GREENE, ANDREW J. COPP
2012 Genetics Research  
The growth of the tooth and alveolar bone is coordinated so that a studied distance always separates the two. We have called this distance, the tooth-bone interface (TBI). Lack of mineralization, a crucial feature of the TBI, creates the space for the developing tooth to grow and the soft tissues of the periodontium to develop. No studies have been done to understand the signals that maintain the bone-free TBI, or the influence of the TBI on tooth development. We have investigated the impact of
more » ... gated the impact of the developing alveolar bone on the size and development of the mouse first molar (M1). We evaluated the growth and osteoclasts distribution of the M1 in explant cultures using two methods, isolation of the M1 from the surrounding alveolar bone, and enhancement of osteoclastogenesis through RANK-RANKL signalling after treatment with RANKL, an osteoclast activator. Both methods showed a significant increase in the size of M1. Our data indicate that alveolar bone and RANKL regulate tooth size without altering development and osteoclasts are indispensable in promoting the formation of the TBI. We intend to further investigate the interactions between the tooth and alveolar bone during development, looking at the roles of other genes involved in TBI formation. Investigating the role of mitochondrial folate metabolism in neural tube defects Folate one-carbon metabolism (FOCM) is a network of reactions that provide one-carbon units for processes vital to cell function, such as de novo biosynthesis of purines and thymidylate for DNA replication and methionine for methylation. FOCM has long been associated with a common group of congenital disorders : neural tube defects (NTDs), in which the neural tube, the embryonic precursor of the brain and spinal cord, fails to close. Evidence from clinical trials and mice models have hinted at the potential roles that FOCM play during neurulation, but the multifactorial nature of NTDs and complexity of FOCM pathways has hampered elucidation of precise causal relationships between the two. We focused on the glycine cleavage system (GCS), a mitochondrial component of the FOCM mediated by four enzymes : GLDC, AMT, GCSH and DLD. Collectively, these enzymes cleave glycine to supply one-carbon units to FOCM reactions occurring in the cytoplasm. Deficiencies in the GCS result in non-ketotic hyperglycinemia, but recent evidence has emerged suggesting that they also predispose to neural tube defects. The aim of this project is to study the effects of GCS deficiency on folate metabolism and the developmental mechanisms underlying NTDs found in Gldc and Amt mice models. In mammals, sex determination is controlled by the inheritance of the Y chromosome. The gonads form at around 10 days post coitum in mice and are bipotential until the expression of the Y-linked testisdetermining gene, Sry. This expression initiates a genetic cascade leading to testis differentiation. We have shown that loss of either Map3k4 or Gadd45c causes male to female sex reversal in XY mouse embryos, due to a delay in Sry expression. We recently showed that those two molecules can act in the same pathway during testis differentiation and regulate the phosphorylation of p38 MAPK and of GATA4, a known regulator of Sry. To better understand the role of this pathway in the control of Sry expression, we are interested in epigenetic modifications at the Sry locus associated with its normal expression profile and whether these are disrupted in mutants. We showed that six CpGs at the Sry promoter are hypomethylated in testis in comparison with extra-gonadal tissues, but this hypomethylation is not affected by loss of Gadd45c or Map3k4. Our present work consists of establishing a protocol for chromatin immunoprecipitation from small numbers of gonadal somatic cells that will allow us to study epigenetic modifications at Sry. Exploring the relationship between kidney pericytes and juxtaglomerular cells
doi:10.1017/s0016672312000572 fatcat:qklgvut6cnafhfxbpf2rlzlwau