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Expression Profiling the Developing Mammalian Enteric Nervous System Identifies Marker and Candidate Hirschsprung Disease Genes

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Expression Profiling the Developing Mammalian Enteric Nervous System Identifies Marker and Candidate Hirschsprung Disease Genes Expression profiling the developing mammalian enteric nervous system identifies marker and candidate Hirschsprung disease genes Tiffany A. Heanue and Vassilis Pachnis* Division of Molecular Neurobiology, National Institute for Medical Research, Medical Research Council, The Ridgeway, Mill Hill, London NW7 1AA, United Kingdom Communicated by Shirley M. Tilghman, Princeton University, Princeton, NJ, March 16, 2006 (received for review January 19, 2006) The enteric nervous system (ENS) is composed of neurons and glial eration, differentiation, and axonogenesis within the ENS (11–13). cells, organized as interconnected ganglia within the gut wall, How Ret signaling regulates these diverse cellular responses re- which controls persistalsis of the gut wall and secretions from its quired for normal ENS development is not understood. glands. The Ret receptor tyrosine kinase is expressed throughout HSCR occurs relatively frequently in the human population enteric neurogenesis and is required for normal ENS development; (1:5,000 live births). Mutations in RET and the Endothelin receptor humans with mutations in the RET locus have Hirschsprung disease type B (EDNRB) account for 50% and 5% of familial HSCR cases, (HSCR, an absence of ganglia in the colon), and mice lacking Ret respectively. Mutations in a number of other genes account for a have total intestinal aganglionosis. The Ret mutant mouse pro- further small percentage of HSCR cases, including the Ret ligands vides a tool for identifying genes implicated in development of the GDNF and NTN, the EDNRB ligand EDN3, the EDN3-converting ENS. By using RNA from WT and Ret mutant (aganglionic) gut tissue enzyme ECE1, SOX10, PHOX2B, and ZFHX1B (7). Additional and DNA microarrays, we have conducted a differential screen for susceptibility loci have been identified, although the corresponding ENS-expressed genes and have identified hundreds of candidate genes have yet to be determined (7). ENS-expressed genes. Forty-seven genes were selected for further The key to understanding the molecular and cellular processes BIOLOGY analysis, representing diverse functional classes. We show that all required for normal ENS development, and the corresponding of the analyzed genes are expressed in the ENS and that the screen defects that lead to HSCR, is an accurate profile of the cellular and DEVELOPMENTAL was sensitive enough to identify genes marking only subpopula- molecular makeup of the ENS. In this study, we have applied DNA tions of ENS cells. Our screen, therefore, was reliable and sensitive microarray techniques to profile gene expression in the developing and has identified many previously undescribed genes for studying ENS. Our screen has identified a large cohort of candidate ENS ENS development. Moreover, two of the genes identified in our marker genes within the mammalian gut, and we have verified the screen Arhgef3 and Ctnnal1, have human homologues that map to ENS expression of a representative subset of genes. The identified previously identified HSCR susceptibility loci, thus representing genes are expressed during ENS migration, proliferation, differen- excellent candidates for HSCR genes. This comprehensive profile of tiation, and axonogenesis and provide a valuable resource for ENS gene expression refines our understanding of ENS develop- further understanding of the cellular events critical for enteric ment and serves as a resource for future developmental, biochem- neurogenesis. Finally, our studies have revealed candidate genes for ical, and human genetic studies. previously characterized HSCR susceptibility loci. microarray ͉ Ret ͉ Sox2 ͉ Arhgef3 ͉ Ctnnal Results Microarray Screen for ENS Expressed Genes. To identify genes he enteric nervous system (ENS) is composed of a vast number expressed during mammalian ENS development we took advantage Tof neurons and glial cells, which form interconnected ganglia of the mouse RetkϪ mutation, which in homozygosity results in total that control the contractility of the smooth muscle of the gut wall intestinal aganglionosis (9, 10). We reasoned that transcripts more and the secretory activity of its glands (1). The ENS is derived from abundantly expressed in Retϩ/ϩ versus RetkϪ/kϪ intestines should vagal and sacral enteric neural crest cells (ENCs), which invade the represent ENS-expressed genes. We therefore isolated RNA from foregut and hindgut, respectively (2, 3). Once situated within the embryonic day 15.5 (E15.5) Retϩ/ϩ and RetkϪ/kϪ intestines, because gut, ENCs migrate along the developing bowel, proliferate, and sufficient amounts of RNA could be isolated at this time point and differentiate to form many different neuronal subtypes and make because genes known to be key ENS development regulators, such synaptic connections (4, 5). Migration of ENCs within the gut as Ret, Grfa1, and Sox10, are expressed at this stage (14). requires signaling between these cells and the gut environment and To enable a broad and unbiased comparison of gene expression depends on dynamic changes in cell shape and adhesive properties. between Retϩ/ϩ and RetkϪ/kϪ intestines, we examined gene expres- How cell shape and adhesion are controlled to allow regulated and sion profiles by using Affymetrix microarrays. Of the Ϸ22,000 probe directed migration of ENCs currently is unknown. Furthermore, sets represented on the array, 372 were expressed more abundantly how cell fate decisions are controlled to specify the correct number in Retϩ/ϩ versus RetkϪ/kϪ intestinal samples, ranging from 89-fold and subtypes of neurons and glial cells within ENS ganglia or how higher to 1.28-fold higher in normal versus aganglionic gut tissue correct synaptic circuits are established also is unknown. (Table 4, which is published as supporting information on the PNAS Genetic studies in mouse and human have identified several web site). The 372 probe sets correspond to 329 distinct genes and genes whose function is required for normal ENS development (6, represent candidate ENS-expressed genes. Consistent with this 7). For example, the Ret receptor tyrosine kinase is expressed in ENCs during migration into the gut and persists during later ENS development (8). Humans carrying mutations in RET develop Conflict of interest statement: No conflicts declared. congenital megacolon [Hirschsprung disease (HSCR) OMIM Abbreviations: En, embryonic day n; ENC, enteric neural crest cell; ENS, enteric nervous 142623; ref. 7], which is characterized by the absence of enteric system; HSCR, Hirschsprung disease; Pn, postnatal day n; RhoGEF, Rho guanine nucleotide ganglia from the colon (colonic aganglionosis), whereas Ret- exchange factor; TF, transcription factor. Ϫ Ϫ deficient mice (Retk /k ) have total intestinal aganglionosis (9, 10). *To whom correspondence should be addressed. E-mail: [email protected]. Ret signaling has been implicated in regulating migration, prolif- © 2006 by The National Academy of Sciences of the USA www.pnas.org͞cgi͞doi͞10.1073͞pnas.0602152103 PNAS ͉ May 2, 2006 ͉ vol. 103 ͉ no. 18 ͉ 6919–6924 Downloaded by guest on September 28, 2021 Table 1. Genes selected for validation by in situ hybridization from the full list of genes on the MOE430A chip more abundantly expressed in Ret؉/؉ versus Retk؊/k؊ intestine Gene Fold change symbol Gene name WT͞MUT Unigene Mapk10 Mitogen-activated protein kinase 10 89.88 Mm.39253 Sncg Synuclein, ␥ 59.42 Mm.282800 Mab21i1 Mab-21-like 1 51.19 Mm.252244 Prph1 Peripherin 33.04 Mm.2477 Ascl1 Achaete-scute complex homolog-like 1 30.99 Mm.136217 Stmn3 Stathmin-like 3 29.01 Mm.2319 Tubb3 Tubulin, ␤3 28.96 Mm.40068 Dlx1 Distal-less homeobox 1 25.29 Mm.4543 Serpini1 Serine (or cysteine) peptidase inhibitor, clade I, member 1 20.19 Mm.41560 Elavl4 ELAV (embryonic lethal, abnormal vision, Drosophila)-like 4 (Hu antigen D) 18.01 Mm.3970 Pcdha Protocadherin ␣ 17.28 Mm.308500 Phox2a Paired-like homeobox 2a 16.83 Mm.358574 Vip Vasoactive intestinal polypeptide 16.17 Mm.98916 Mapt Microtubule-associated protein ␶ 16.05 Mm.1287 Elavl2 ELAV (embryonic lethal, abnormal vision, Drosophila)-like 2 (Hu antigen B) 15.16 Mm.318042 Stmn2 Stathmin-like 2 14.37 Mm.29580 Sox10 SRY-box containing gene 10 12.53 Mm.276739 Sox2 SRY-box containing gene 2 10.97 Mm.4541 Uchl1 Ubiquitin carboxyl-terminal hydrolase PGP9.5 10.77 Mm.29807 Dcx Doublecortin 10.72 Mm.12871 Tagln3 Transgelin 3 9.968 Mm.24183 Ebf3 Early B cell factor 3 9.837 Mm.258708 Cart Cocaine and amphetamine regulated transcript 9.657 Mm.75498 Nsg2 Neuron-specific gene family member 2 8.049 Mm.3304 Gap43 Growth-associated protein 43 7.615 Mm.1222 Hmx3 H6 homeobox 3 7.291 Mm.323562 Syt11 Synaptotagmin XI 7.061 Mm.379376 Scg3 Secretogranin III 6.567 Mm.2386 Arhgef3 Rho guanine nucleotide exchange factor 3 6.191 Mm.248606 Phox2b Paired-like homeobox 2b 6.098 Mm.62505 Gng3 Guanine nucleotide binding protein (G protein), ␥3 subunit 5.623 Mm.329700 Hoxb5 Homeobox B5 5.298 Mm.207 Hoxd4 Homeobox D4 5.219 Mm.1214 Dpysl3 Dihydropyrimidinase-like 3 5.181 Mm.8180 Tmeff2 Transmembrane protein with EGF-like and two follistatin-like domains 2 4.936 Mm.245154 Fgf13 Fibroblast growth factor 13 4.827 Mm.7995 Crmp1 Collapsin response mediator protein 1 4.386 Mm.290995 Gng2 Guanine nucleotide-binding protein (G protein), ␥2 subunit 3.988 Mm.41737 Mllt11 Myeloid͞lymphoid or mixed-lineage leukemia (tri-thorax homolog 4.222 Mm.331208 Drosophila) translocated to 11 Igsf4a Immunoglobulin superfamily, member 4A 3.42 Mm.234832 Cdh2 Cadherin 2 3.279 Mm.257437 L1cam L1 cell adhesion molecule 2.807 Mm.260568 Gfra1 Glial cell line-derived neurotrophic factor family receptor ␣1 2.772 Mm.88367 Tgfb2 Transforming growth factor, ␤2 2.326 Mm.18213 Ret Ret proto-oncogene 1.913 Mm.57199 Etv1 Ets variant gene 1 1.885 Mm.4866 Tbx3 T-box 3 1.812 Mm.219139 Genes from the full list of genes on the MOE430A chip more abundantly expressed in Retϩ͞ϩ versus RetkϪ͞kϪ intestine (Table 3) were selected for validation by RNA in situ hybridization on tissue sections (Fig.
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