Investigation of the Functional Role of BMP Signaling in Zebrafish ENS Development Open Access

Abstract

Investigation of the Functional Role of BMP Signaling in ENS Development
The Enteric Nervous System (ENS) is the set of neurons and glia that comprises the
nervous system in your intestine, allowing for complex control of gastrointestinal (GI)
function. A properly constructed ENS requires sufficient proliferation followed by
appropriate differentiation of these enteric precursors, which all derive from an axial
population of cells called the vagal neural crest. If the precursors fail to populate the gut
in sufficient numbers and fail to differentiate into the appropriate neuronal and glial
subtypes, it can cause various congenital disorders, one of which is Hirschsprung's
(HSCR) Disease. HSCR is a pediatric developmental disorder occurring in approximately
1:5000 live births. The genetic basis of HSCR is only partially understood. To identify
new HSCR genes we utilize the zebrafish model system. Previously the Shepherd lab
identified a zebrafish ENS mutant with an HSCR-like phenotype that was named lessen
( lsn). In subsequent analysis of this mutant, a number of components of the Bone
Morphogenic Protein (BMP) signaling pathway were differentially expressed. The BMP
pathway is known to be involved in various developmental processes and has been
implicated in ENS development. Given these results we aimed to determine the spatial
and temporal expression pattern of the BMP ligands in the developing zebrafish intestine
by in situ hybridizations. We then determined the effect of inhibiting BMP signaling on
zebrafish ENS development. We find that treatment with a small molecule inhibitor of
the BMP pathway, DMH1 at stages of ENS development when neural precursors would
normally be differentiating, causes an increase in the number of enteric neurons at
120hpf. We propose a model of BMP-regulated ENS development in which BMP
signaling determines different developmental choices depending on the amount of BMP
signaling in the intestine at specific developmental stages. Early in zebrafish ENS
development low levels of BMP signaling maintain ENS precursors in a proliferative state

while levels of BMP signaling at later stages of ENS development causes precursor differentiation.

Table of Contents

Table of Contents
Introduction 1-12

Gastrointestinal Tract 1

Enteric Nervous System Development 1

Hirschprung's Disease 4

Zebrafish model System 5

ENS in Zebrafish 6

lessen mutatnts 7

Bone Morphogeneic Protein Pathway 8

BMP Pathway in ENS Development 9

Materials and Methods 12-14

Results and Discussion 14-28

Expression of BMP Signaling Components 14

Dose Response Curve 16

ENS Development in DMH1 Treated Embryos 18

Effect OF DMH1 on Smooth Muscle Development 24

Conclusions 28-31

References 32-34

About this Honors Thesis

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School	Emory College
Department	Biology
Degree	BS
Submission	Honors Thesis
Language	English
Research Field	Biology, Neuroscience Biology, General
Keyword	Hirschpring's Disease enteric nervous system zebrafish
Committee Chair / Thesis Advisor	Shepherd, Iain, Emory University
Committee Members	Srinivasan, Shanthi, Emory University Fritz, Andreas, Emory University

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