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3 results on '"Maccoll G"'

1. The role of insulin receptor substrate 2 in hypothalamic and beta cell function.

Author

Choudhury AI, Heffron H, Smith MA, Al-Qassab H, Xu AW, Selman C, Simmgen M, Clements M, Claret M, Maccoll G, Bedford DC, Hisadome K, Diakonov I, Moosajee V, Bell JD, Speakman JR, Batterham RL, Barsh GS, Ashford ML, and Withers DJ

Subjects
Animals, Body Weight, Electrophysiology, Genotype, Glucose metabolism, Hypothalamus cytology, Insulin administration & dosage, Insulin metabolism, Insulin Receptor Substrate Proteins, Intracellular Signaling Peptides and Proteins, Islets of Langerhans cytology, Leptin administration & dosage, Leptin metabolism, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Neurons cytology, Phosphoproteins genetics, Pro-Opiomelanocortin metabolism, Receptor, Insulin metabolism, Recombinant Fusion Proteins genetics, Recombinant Fusion Proteins metabolism, Energy Metabolism, Homeostasis, Hypothalamus metabolism, Islets of Langerhans metabolism, Neurons metabolism, Phosphoproteins metabolism
Abstract

Insulin receptor substrate 2 (Irs2) plays complex roles in energy homeostasis. We generated mice lacking Irs2 in beta cells and a population of hypothalamic neurons (RIPCreIrs2KO), in all neurons (NesCreIrs2KO), and in proopiomelanocortin neurons (POMCCreIrs2KO) to determine the role of Irs2 in the CNS and beta cell. RIPCreIrs2KO mice displayed impaired glucose tolerance and reduced beta cell mass. Overt diabetes did not ensue, because beta cells escaping Cre-mediated recombination progressively populated islets. RIPCreIrs2KO and NesCreIrs2KO mice displayed hyperphagia, obesity, and increased body length, which suggests altered melanocortin action. POMCCreIrs2KO mice did not display this phenotype. RIPCreIrs2KO and NesCreIrs2KO mice retained leptin sensitivity, which suggests that CNS Irs2 pathways are not required for leptin action. NesCreIrs2KO and POMCCreIrs2KO mice did not display reduced beta cell mass, but NesCreIrs2KO mice displayed mild abnormalities of glucose homeostasis. RIPCre neurons did not express POMC or neuropeptide Y. Insulin and a melanocortin agonist depolarized RIPCre neurons, whereas leptin was ineffective. Insulin hyperpolarized and leptin depolarized POMC neurons. Our findings demonstrate a critical role for IRS2 in beta cell and hypothalamic function and provide insights into the role of RIPCre neurons, a distinct hypothalamic neuronal population, in growth and energy homeostasis.

Published
2005
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2. GnRH neuronal development: insights into hypogonadotrophic hypogonadism.

Author

MacColl G, Quinton R, and Bouloux PM

Subjects
Animals, Central Nervous System physiology, Gonadotropin-Releasing Hormone analogs & derivatives, Humans, Hypogonadism etiology, Hypogonadism genetics, Kallmann Syndrome complications, Kallmann Syndrome genetics, Kallmann Syndrome physiopathology, Olfaction Disorders genetics, Olfaction Disorders physiopathology, Cell Movement physiology, Gonadotropin-Releasing Hormone physiology, Hypogonadism physiopathology, Neurons physiology
Abstract

Pulsatile secretion of the hypothalamic decapeptide gonadotrophin-releasing hormone (GnRH) regulates activity of the pituitary-gonadal reproductive axis. Defects of this neuroendocrine axis necessarily result in hypogonadotrophic hypogonadism. In many vertebrate species studied, the main population of GnRH neurones originates extracranially within the olfactory system. In humans, both olfactory and GnRH systems are affected in Kallmann's syndrome--resulting in isolated hypogonadotrophic hypogonadism (IHH) combined with anosmia (loss of sense of smell). Familial IHH is also caused by other genetic conditions, which prevent GnRH from activating luteinizing hormone/follicle-stimulating hormone release from pituitary gonadotrophs. However, many cases of IHH have no defined chromosomal abnormality and, in the absence of pedigree analysis, studying the biological mechanisms controlling migration of GnRH neurones through the olfactory system into the developing central nervous system might reveal additional genetic pathways that play a role in the pathogenesis of IHH.

Published
2002
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3. Molecular modelling and experimental studies of mutation and cell-adhesion sites in the fibronectin type III and whey acidic protein domains of human anosmin-1

Author

Robertson, A, MacColl, G S, Nash, J A, Boehm, M K, Perkins, S J, and Bouloux, P M

Subjects
Models, Molecular, Neurons, Extracellular Matrix Proteins, Sequence Homology, Amino Acid, Protein Conformation, Amino Acid Motifs, DNA Mutational Analysis, Molecular Sequence Data, Mutation, Missense, Nerve Tissue Proteins, Milk Proteins, Fibronectins, Protein Structure, Tertiary, Amino Acid Substitution, Cell Adhesion, Humans, Amino Acid Sequence, Heparitin Sulfate, Peptides, Cells, Cultured, Research Article
Abstract

Anosmin-1, the gene product of the KAL gene, is implicated in the pathogenesis of X-linked Kallmann's syndrome. Anosmin-1 protein expression is restricted to the basement membrane and interstitial matrix of tissues affected in this syndrome during development. The anosmin-1 sequence indicates an N-terminal cysteine-rich domain, a whey acidic protein (WAP) domain, four fibronectin type III (FnIII) domains and a C-terminal histidine-rich region, and shows similarity with cell-adhesion molecules, such as neural cell-adhesion molecule, TAG-1 and L1. We investigated the structural and functional significance of three loss-of-function missense mutations of anosmin-1 using comparative modelling of the four FnIII and the WAP domains based on known NMR and crystal structures. Three missense mutation-encoded amino acid substitutions, N267K, E514K and F517L, were mapped to structurally defined positions on the GFCC' beta-sheet face of the first and third FnIII domains. Electrostatic maps demonstrated large basic surfaces containing clusters of conserved predicted heparan sulphate-binding residues adjacent to these mutation sites. To examine these modelling results anosmin-1 was expressed in insect cells. The incorporation of the three mutations into recombinant anosmin-1 had no effect on its secretion. The removal of two dibasic motifs that may constitute potential physiological cleavage sites for anosmin-1 had no effect on cleavage. Peptides based on the anosmin-1 sequences R254--K285 and P504--K527 were then synthesized in order to assess the effect of the three mutations on cellular adhesion, using cell lines that represented potential functional targets of anosmin-1. Peptides (10 microg/ml) incorporating the N267K and E514K substitutions promoted enhanced adhesion to 13.S.1.24 rat olfactory epithelial cells and canine MDCK1 kidney epithelial cells (P

Published
2001

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