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Development of Enteric Neurons and Muscularis Macrophages Marina Avetisyan Washington University in St

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Development of Enteric Neurons and Muscularis Macrophages Marina Avetisyan Washington University in St Washington University in St. Louis Washington University Open Scholarship Arts & Sciences Electronic Theses and Dissertations Arts & Sciences Spring 5-15-2019 Development of Enteric Neurons and Muscularis Macrophages Marina Avetisyan Washington University in St. Louis Follow this and additional works at: https://openscholarship.wustl.edu/art_sci_etds Part of the Allergy and Immunology Commons, Immunology and Infectious Disease Commons, Medical Immunology Commons, and the Neuroscience and Neurobiology Commons Recommended Citation Avetisyan, Marina, "Development of Enteric Neurons and Muscularis Macrophages" (2019). Arts & Sciences Electronic Theses and Dissertations. 1781. https://openscholarship.wustl.edu/art_sci_etds/1781 This Dissertation is brought to you for free and open access by the Arts & Sciences at Washington University Open Scholarship. It has been accepted for inclusion in Arts & Sciences Electronic Theses and Dissertations by an authorized administrator of Washington University Open Scholarship. For more information, please contact [email protected]. WASHINGTON UNIVERSITY IN ST. LOUIS Division of Biology and Biomedical Sciences Neurosciences Dissertation Examination Committee: Robert O. Heuckeroth, Chair Aaron DiAntonio, Co-Chair Paul Bridgman Joseph Dougherty Kelly Monk Development of Enteric Neurons and Muscularis Macrophages. by Marina Avetisyan A dissertation presented to The Graduate School of Washington University in partial fulfillment of the requirements for the degree of Doctor of Philosophy May 2019 St. Louis, Missouri © 2019, Marina Avetisyan Table of Contents List of Figures ...................................................................................................................................... vi List of Tables ......................................................................................................................................viii Acknowledgments ............................................................................................................................... ix Abstract .................................................................................................................................................xi Chapter 1: Introduction ......................................................................................................................... 1 Chapter 2: Building a Second Brain in the Bowel ………………………………………...…………..3 2.1 Abstract ………………………………………………………………………………………...….3 2.2 Introduction …………………………………………………………………………………….….3 2.3 ENS morphogenesis …………………………………………………………………………….…4 2.4 Retinoids, RET, and bowel colonization ………………………………………………………….5 2.5 Cell proliferation and bowel colonization ………………………………………………………...8 2.6 Chain Migration and Cell Adhesion ………………………………………………………………8 2.7 Intracellular signaling and Migration …………………………………………………………..…9 2.8 ENS morphogenesis does not end when ENCDC reach “The End”… ………………………….11 2.9 Neuronal subtype specification .. ……………………………………………………………..…12 2.10 Axon pathfinding and synaptogenesis: A tangled web of neurites …………………………..…17 2.11 Clinical implications ………………………………………………………………………...….18 2.12 Acknowledgements …………………………………………………………………………..…19 2.13 References….……………………………………………………………………………………21 Chapter 3: HGF and Met support mouse enteric nervous system development, the peristaltic response, and intestinal epithelial proliferation in response to injury ……………………30 3.1 Abstract ………………………………………………………………………………………………………………………………….30 3.2 Introduction ……………………………………………………………………………………………………………………………31 3.3 Materials and Methods ……………………………………………………………………………………………………………33 ii 3.3.1 Animals ……………………………………………………………………………………………………………………………….33 3.3.2 Antibodies and reagents ……………………………………………………………………………………………………….33 3.3.3 Quantitative ENS analysis ………………………………………………………………………………………………..….34 3.3.4 Immunohistochemistry and image processing ………………………………………………………………….….35 3.3.5 Human gut ……………………………………………………………………………………………………………………….….35 3.3.6 DiI Labeling combined with immunohistochemistry ……………………………………………………….35 3.3.7 Dissociated cell culture ………………………………………………………………………………………………….….36 3.3.8 Slice culture ……………………………………………………………………………………………………………………….36 3.3.9 In vitro peristaltic response ……………………………………………………………………………………………….37 3.3.10 Whole Gastrointestinal Transit Assay …………………………………………………………………………….37 3.3.11 Colon Motility Assay ………………………………………………………………………………………………………37 3.3.12 Small Intestine Transit Assay ………………………………………………………………………………………….38 3.3.13 Dextran sodium sulfate (DSS) injury …………………………………………………………………………………38 3.3.14 Quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) ……………………….…39 3.3.15 Statistical analysis …………………………………………………………………………………………………………..…39 3.4 Results …………………………………………………………………………………………………………………………………....40 3.4.1 Met and HGF are expressed in a subset of adult enteric neurons. ……………………………………..…41 3.4.2 HGF and Met signaling support fetal ENS neurogenesis and neurite growth in vitro …...……43 3.4.3 HGF/Met signaling enhances ENS precursor differentiation into neurons in vitro. .………….47 3.4.4 HGF/MET signaling did not increase ENS precursor migration in vitro ……………………...48 3.4.5 MET inactivation within ENS precursors causes selective defects in Met expressing enteric neurons. .…………………………………………………………………….………………………………………………………...48 3.4.6 Functional analysis of gut motility ……………………………………………………………………………………….53 3.4.7 HGF/Met signaling and bowel injury …………………………………………………………………………………….55 3.4.8 GDNF/RET signaling increased Met and Etv5 mRNA in cultured ENS precursors, but MET protein levels in vivo do not depend on Etv5/Etv4 …………………………………………………………..….55 3.5 Discussion ………………………………………………………………………………………………………………………………59 3.5.1 HGF, MET, GDNF and RET …………………………………………………………………………………………….…59 3.5.2 HGF/MET and ENS Development ………………………………………………………………………………………60 iii 3.5.3 HGF/MET and IPAN Subtypes ………………………………………………………………………………………..….61 3.5.4 HGF, the ENS, and intestinal injury …………………………………………………………………………………….62 3.6 Acknowledgements …………………………………………………………………………………………………………….….64 3.7 References …………………………………………………………………………………………………………………………..…65 Chapter 4: Axon Pathfinding in the enteric nervous system ..……………………………………………………..…75 4.1 Introduction ……………………………………………………………………………………………………………………………75 4.2 Materials and Methods ……………………………………………………………………………………………………………78 4.2.1 Animals …………………………………………………………………………………………………………………………….…78 4.2.2 Antibodies and reagents . …………………………………………………………………………………………………..…78 4.2.3 Fluorescence activated cell sorting (FACS) of ENCDC …………………………………………………….…79 4.2.4 Microarray and analysis …………………………………………………………………………………………………….…79 4.2.6 Image acquisition and ENS quantification . ……………………………………………………………………….…80 4.3 Results ……………………………………………………………………………………………………………………………………81 4.3.1 Identification of genes with known roles in axon guidance that are enriched in the developing ENS. ……………………………………………………………………………………………………………………………………81 4.3.2 In situ hybridization (ISH) and imunohistochemistry (IHC) characterization of Plexin A4 in the ENS …………………………………………………………………………………………………………………………………81 4.3.3 Plexin A4 KO mice have no gross defects in ENS fiber patterning or neuron number …….…87 4.3.4 Plexin A4 KO mice have an intact peristalsis reflex ………………………………………………………….…92 4.4 Discussion ……………………………………………………………………………………………………………………………....95 4.4.1 Novel axon guidance genes in the ENS ……………………………………………………………………………..…95 4.4.2 Plexin A4 signaling in the ENS ……………………………………………………………………………………………97 4.4.3 ENS connectivity and disease …………………………………………………………………………………………..….98 4.5 Acknowledgements ………………………………………………………………………………………………………………....99 4.6 References…………………………………………………………………………………………………………………………...100 Chapter 5: Muscularis macrophage development and the ENS ………………………………………………..….107 5.1 Introduction ……………………………………………………………………………………………………………………….…107 5.2 Materials and Methods .. ………………………………………………………………………………………………………..110 5.2.1 Animals …………………………………………………………………………………………………………………………..…110 iv 5.2.2 Generation of Ednrb-GFP-L10a mice …………………………………………………………………………………110 5.2.3 Antibodies and reagents ………………………………………………………………………………………………….…111 5.2.4 Whole mount muscularis externa preparation and immunohistochemistry ……………….…111 5.2.5 Image acquisition and analysis for in situ quantification of muscularis macrophages …….…112 5.2.6 Flow cytometric analysis of muscularis macrophages from P0 bowel …………………….…112 5.2.7 Ex vivo LPS stimulation ………………………………………………………………………………………………….…112 5.2.8 qRT-PCR ………………………………………………………………………………………………………………………..…113 5.3 Results …………………………………………………………………………………………………………………………………..115 5.3.1 Muscularis externa colonization by muscularis macrophages during development does not require enteric neural crest derived cells (ENCDC) ………………………….………………………….…115 5.3.2 The developing bowel contains a non-neuronal source of the muscularis macrophage survival factor, CSF1. ………………..………………………………………………………………………………………..…117 5.3.3 Absence of enteric neurons does not affect the surface phenotype or baseline activation state of neonatal muscularis macrophages ….……………………………………………………………………………..…117 5.3.4 Muscularis macrophages from neonatal mice lacking enteric neurons did not differ from control mice in their activation by LPS stimulation ……………………………………………………………………...119 5.3.5 Maintenance of the muscularis macrophage population in the steady state adult bowel does not require CCR2-mediated monocyte recruitment from bone marrow …………………………121 5.4 Discussion ………………………………………………………………………………………………………………………….
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