Enteric Nervous System Development
My laboratory is interested in the development of the enteric nervous system (ENS), a complex neuronal network whose principal function is to maintain normal intestinal motility. Congenital abnormalities of the ENS are responsible for severe gastrointestinal disorders in childhood, including Hirschsprung’s disease, intestinal pseudo-obstruction, and other causes of dysmotility. The ENS is made up of neurons and glia that arise from the neural crest and migrate along the length of the intestine.
12 day-old embryonic chick intestine labeled with a neuronal antibody (Hu, green) and a neural crest cell antibody (HNK, red)
In our laboratory we use the avian embryo as a model system to study ENS development. Using a variety of techniques, including retroviral-mediated gene misexpression, chick-quail chimeras, coelomic transplantation, and organ culture techniques, we have thoroughly characterized normal development of the colorectal ENS. We have also identified essential roles for bone morphogenetic proteins and endothelin-3 during ENS formation in the hindgut, the portion of intestine most commonly affected in human congenital disorders of the ENS. Ongoing projects include:
Understanding the molecular factors required for normal ENS development will give us new insights into the pathophysiology of neuro-intestinal disorders and allow us to develop novel diagnostic and therapeutic approaches to the management of children with these serious conditions.
Clinical / Translational Research
Chimeric enteric ganglion composed of cells derived from both chick and quail embryos
Constipation is a common complaint in pediatrics, accounting for 25% of all visits to a pediatric gastroenterologist. While the majority of children improve with diet modification or medications, some suffer from severe constipation that does not respond to conventional therapy. These children often suffer from abdominal pain and bloating, fecal incontinence, absence from school, frequent hospitalizations, and social withdrawal. One of the major causes of this intractable constipation is abnormal colonic motility, where the colon is unable to propel waste products out of the body. This problem is seen in slow transit constipation, irritable bowel syndrome, Hirschsprung’s disease, and other disorders of colonic function. Many individuals of all ages are affected by these conditions. However, despite its prevalence, little is known about the causes of abnormal colonic motility and, as a result, available treatments are limited.
Similarly, children with Hirschsprung’s disease can suffer from severe constipation and bloating even after they have had surgery to remove the part of the colon lacking nerve cells. Their symptoms, which can be severe and very difficult to treat, are often due to abnormal colonic motility or to abnormal anorectal function. In severe cases, children with Hirschsprung’s can develop enterocolitis, a life-threatening inflammation of the intestine. As in other conditions caused by abnormal intestinal motility, the causes are unknown and treatment options are limited.
Intestinal neurons labeled with a neuronal antibody (Tuj1) in red, with their nuclei stained blue (DAPI), form elaborate neuronal networks in vitro.
Goldstein AM, Ticho BS, Fishman MC. Patterning the heart’s left-right axis: from zebrafish to man. Developmental Genetics 1998; 22:278-287. (Pubmed 9621434)
Goldstein AM, Fishman MC. Notochord regulates cardiac lineage in zebrafish embryos. Developmental Biology 1998; 201:247-252. (Pubmed ID 9740662)
Kennedy DN, O’Craven KM, Ticho BS, Goldstein AM, Makris N, Henson JW. Structural and functional brain asymmetries in human situs inversus totalis. Neurology 1999; 53: 1260-1265. (Pubmed ID 10522882)
Ticho BS, Goldstein AM, Van Praagh R. Extracardiac anomalies in the heterotaxy syndromes with focus on anomalies of midline-associated structures. American Journal of Cardiology 2000; 85:729-734. (Pubmed ID 12000048)
Chen JN, van Bebber F, Goldstein AM, Serluca FC, Jackson D, Childs S, Serbedzija G, Warren KS, Mably JD, Lindahl P, Mayer A, Haffter P, Fishman MC. Genetic steps to organ laterality in zebrafish. Comparative and Functional Genomics 2001; 2:60-68. (Pubmed ID 18628903)
Doyle AM, Roberts DJ, Goldstein AM. Enteric nervous system patterning in the avian hindgut. Developmental Dynamics 2004; 229:708-712. (Pubmed ID 14991727)
Goldstein AM, Brewer KC, Doyle AM, Nagy N, Roberts DJ. BMP signaling is necessary for neural crest cell migration and ganglion formation in the enteric nervous system. Mechanisms of Development 2005; 122:821-833. (Pubmed ID 15905074)
de Santa Barbara P, Williams J, Goldstein AM, Doyle AM, Nielsen C, Winfield S, Faure S, Roberts DJ. BMP signaling pathway plays multiple roles during gastrointestinal tract development. Developmental Dynamics 2005; 234:312-322. (Pubmed ID 16110505)
Brewer KC, Mwizerva O, Goldstein AM. BMPRIA is a promising marker for evaluating ganglion cells in the enteric nervous system – a pilot study. Human Pathology 2005; 36:1120-1126. (Pubmed ID 16226113)
Nagy N, Goldstein AM. Endothelin-3 regulates neural crest cell proliferation and differentiation in the hindgut enteric nervous system. Developmental Biology 2006; 293:203-217. (Pubmed ID 16519884)
Nagy N, Goldstein AM. Intestinal coelomic transplants: a novel method for studying enteric nervous system development. Cell and Tissue Research 2006; 326:43-55. (Pubmed ID 16736197)
Nagy N, Brewer KC, Mwizerwa O, Goldstein AM. Pelvic plexus contributes ganglion cells to the hindgut enteric nervous system. Developmental Dynamics 2007; 236:73-83. (Pubmed ID 16937371)
Beppu H, Mwizerwa ON, Beppu Y, Dattwyler MP, Lauwers GY, Bloch KD, Goldstein AM. Stromal inactivation of BMPRII leads to colorectal epithelial overgrowth and polyp formation. Oncogene 2008; 27:1063-1070. (Pubmed ID 17700526)
Irani K, Rogriduez L, Doody DP, Goldstein AM. Botulinum toxin for the treatment of chronic constipation in children with internal anal sphincter dysfunction. Pediatric Surgery International 2008;24:779-783. (Pubmed ID 18443801)
Goldstein AM, Nagy N. A bird’s eye view of enteric nervous system development: lessons from the avian embryo. Pediatric Research 2008;64:326-333. (Pubmed ID 18636038)
Field HA, Kelley KA, Martell L, Goldstein AM, Serluca FC. Analysis of gastrointestinal physiology using a novel intestinal transit assay in zebrafish. Neurogastroenterology & Motility 2009;21:304-312. (Pubmed ID 19140958)
Nagy N, Mwizerwa O, Yaniv K, Carmel L, Pieretti-Vanmarcke R, Weinstein BM, Goldstein AM. Endothelial cells promote migration and proliferation of enteric neural crest cells via b1 integrin signaling. Developmental Biology 2009;330:263-272. (Pubmed ID 19345201)
Christison-Lagay ER, Rodriguez L, Kurtz M, St. Pierre K, Doody DP, Goldstein AM. Antegrade colonic enemas and intestinal diversion are highly effective in the management of children with intractable constipation. Journal of Pediatric Surgery 2010;45:213-219.
Pieretti RV, Goldstein AM, Pieretti-Vanmarcke R. Late complications of newborn circumcision: a common and avoidable problem. Pediatric Surgery International 2010;26:515-518.
Rodriguez L, Flores A, Gilchrist BF, Goldstein AM. Laparoscopic-assisted percutaneous endoscopic cecostomy (LAPEC). Gastrointestinal Endoscopy 2011;73:98-102.
Nanthakumar N, Meng D, Goldstein AM, Zhu W, Lu L, Uauy R, Llanos EC, Walker WA. The mechanism of excessive intestinal inflammation in necrotizing enterocolitis: An immature innate immune response. PLoS ONE 2011;6(3):e17776.
Nehra D, Goldstein AM. Intestinal malrotation: varied clinical presentation from infancy through adulthood. Surgery 2011;149:386-393.
Mwizerwa O, Das P, Nagy N, Akbareian SE, Mably JD, Goldstein AM. Gdnf is mitogenic, neurotrophic, and chemoattractive to enteric neural crest cells in the embryonic colon. Developmental Dynamics 2011;240:1402-1411.
Rodriguez L, Irani K, Jiang H, Goldstein AM. Clinical presentation, response to therapy, and outcome of gastroparesis in children. Journal of Pediatric Gastroenterology & Nutrition (in press).
Melendez E, Goldstein AM, Sagar P, Badizadegan K. Case 3-2012: A newborn boy with vomiting, diarrhea, and abdominal distension. New England Journal of Medicine 2012;366:361-372.
Auksorius E, Bromberg Y, Motiejunaite R, Pieretti A, Liu L, Coron E, Aranda J, Goldstein AM, Bouma BE, Kazlauskas A, Tearney GJ. Dual-modality fluorescence and full-field optical coherence microscopy for biomedical imaging applications. Biomedical Optics Express 2012;3:661-666.
Nagy N, Burns AJ, Goldstein AM. Immunophenotypic characterisation of enteric neural crest cells in the developing avian colorectum. Developmental Dynamics 2012;241:842-851
Ward NL, Pieretti A, Dowd SE, Cox SB, Goldstein AM. Intestinal aganglionosis is associated with early and sustained disruption of the colonic microbiome. Neurogastroenterology & Motility 2012;24:874-e400.
Belkind-Gerson J, Goldstein AM, Kuo B. Balloon expulsion test as a screen for outlet obstruction in children with chronic constipation. Journal of Pediatric Gastroenterology & Nutrition 2012 (in press).
Coron E, Pieretti A, Auksorius E, Mahe MM, Liu L, Steiger C, Bromberg Y, Bouma B, Tearney G, Neunlist M, Goldstein AM. Full-field optical coherence microscopy (FFOCM) is a novel technique for imaging enteric ganglia in the gastrointestinal tract. Neurogastroenterology & Motility 2012;24:e611-621.
Belkind-Gerson J, Carreon A, Benedict LA, Steiger C, Pieretti A, Nagy N, Dietrich J, Goldstein AM. Nestin-expressing cells in the gut give rise to enteric neurons and glial cells. Neurogastroenterology & Motility 2013;25:61-69.
Goldstein AM, Hofstra RMW, Burns AJ. Building a brain in the gut: development of the enteric nervous system. Clinical Genetics 2013;83:307-316.
Rodriguez L, Roberts LD, LaRosa J, Heinz N, Gerszten R, Nurko S, Goldstein AM. Relationship between postprandial metabolomics and colon motility in children with constipation Neurogastroenterology & Motility (in press).
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