[A 3D cell network which brings out relief in the pituitary gland].
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Animals↗
Biomedical subjects
Patrice Mollard
Publications and source records attributed to Patrice Mollard.
Revealing the large-scale network organization of growth hormone-secreting cells.
Pituitary growth hormone (GH)-secreting cells regulate growth and metabolism in animals and humans. To secrete highly ordered GH pulses (up to 1,000-fold rise in hormone levels in vivo), the pituitary GH cell population needs to mount coordinated responses to GH secretagogues, yet GH cells display an apparently heterogeneous scattered distribution in 2D histological studies. To address this paradox, we analyzed in 3D both positioning and signaling of GH cells using reconstructive, two-photon excitation microscopy to image the entire pituitary in GH-EGFP transgenic mice. Our results unveiled a homologous continuum of GH cells connected by adherens junctions that wired the whole gland and exhibited the three primary features of biological networks: robustness of architecture across lifespan, modularity correlated with pituitary GH contents and body growth, and connectivity with spatially stereotyped motifs of cell synchronization coordinating cell activity. These findings change our view of GH cells, from a collection of dispersed cells to a geometrically connected homotypic network of cells whose local morphology and connectivity can vary, to alter the timing of cellular responses to promote more coordinated pulsatile secretion. This large-scale 3D view of cell functioning provides a powerful approach to identify and understand other networks of endocrine cells that are thought to be scattered in situ. Many dispersed endocrine systems exhibit pulsatile outputs. We suggest that cell positioning and associated cell-cell connection mechanisms will be critical parameters that determine how well such systems can deliver a coordinated secretory pulse of hormone to their target tissues.
Animals↗
Amino-acid changes acquired during evolution by olfactory receptor 912-93 modify the specificity of odorant recognition.
The sense of smell in mammals can perceive and discriminate a wide variety of volatile odorants. Odorants bind to specific olfactory receptors (ORs) to initiate an action potential that transduces olfactory information to the olfactory cortex. We previously identified the structural motifs of odorant molecules (aliphatic 2- or 3-ketones) required to activate mouse OR912-93 by detection of the odorant response using calcium measurement in transfected cells. In order to study changes in the specificity of this receptor that might have occurred during evolution, we cloned the orthologous genes from six primate species and pig and assayed the encoded receptors for responses to odorants. Primate OR912-93 orthologs share 88-97% sequence identity. All the receptors responded to 2- and 3-heptanone except the squirrel-monkey OR, which responded only to 3-heptanone, and the human and orangutan ORs, which were not functional. Directed mutagenesis allowed us to convert the squirrel-monkey response to that of the other functional 912-93 ORs by substituting three amino acids in the second extracellular loop. Orangutan and human 912-93 ORs regained function after restoration of the arginine residue in the DRY motif required for G-protein activation. However, the human receptor was constitutively activated in the absence of ligand stimulation. Using natural mutants of the OR912-93 receptor, we provide evidence that squirrel-monkeys evolved towards a restriction of the specificity of this receptor and therefore that slight alterations in the sequence of a receptor can induce subtle changes in recognition specificity.
Amino Acid Motifs↗
Electrical activity in endocrine pituitary cells in situ: a support for a multiple-function coding.
The anterior pituitary is an endocrine gland that controls basic body functions. Pituitary cell functioning depends on membrane excitability, which induces cytosolic calcium rises. Here, we reported the first identification of small-amplitude voltage fluctuations that controlled spike firing in endocrine cells recorded in situ. Three patterns of voltage fluctuations were distinguishable by their durations (1-100 s). These patterns could be ordered on top of each other, namely in response to secretagogues. Thus, pituitary endocrine cells express in situ a cell code in which small-amplitude voltage fluctuations lead to a multimodal arrangement of spike firing, which may finely tune calcium-dependent functions.
Action Potentials↗
Hidden face of the anterior pituitary.
The traditional view holds that the anterior pituitary is an endocrine gland with a complex and heterogeneous distribution of cells throughout the parenchyma. Thus, a long-distance mode of intraorgan communication is not usually taken into account in our understanding of pituitary functioning. However, recent in situ pituitary studies have begun to unveil a hitherto unknown route of large-scale information transfer within the pituitary. Agranular folliculostellate cells - the sixth type of pituitary cell initially discovered almost half a century ago - are the functional units of a dynamically active cell network wiring the whole gland. Because folliculostellate cells communicate with their endocrine neighbors, this opens the door to considering the pituitary as a cellular puzzle more ordered than was first thought. Hence, cell networking within the pituitary gland could have a privileged role in coordinating the activities of distant cells in both physiological and pathological conditions.
Animals↗
A single olfactory receptor specifically binds a set of odorant molecules.
The sense of smell is mediated by the initiation of action potential in olfactory sensory neurons during odor stimulation. However, little is known about odorant-olfactory receptor (OR) recognition mechanisms. In the present work, we identified the structural motifs of odorant molecules required to activate mouse OR912-93 by detection of the odorant response using calcium measurement in cells transfected with OR and G(alpha)q and G(alpha)15 proteins. The use of sets of odorants led to the identification of ketones with an aliphatic carbon chain length >or= four carbon atoms and a carbonyl group preferentially located in position C2 or C3. The threshold of detection of these odorants is as low as 10(-6)-10(-8)m. No other odorant ligand, out of 70 representatives of the odorant world, was active. The human ortholog of OR912-93 is not functional, suggesting that apart from a stop-mutation located at the 5'-end that was corrected in the construct, it incurred other deleterious mutations during evolution.
Animals↗