Building a second brain in the bowel

Avetisyan, Marina; Schill, Ellen Merrick; Heuckeroth, Robert O.

doi:10.1172/jci76307

Cited by 116 publications

(74 citation statements)

References 137 publications

(155 reference statements)

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“…HSCR risk, however, remains challenging to define because so many genetic and nongenetic factors influence signaling pathways that control ENCDC survival, proliferation, differentiation, and migration (5), leading to complex gene-gene (25) and gene-environment interactions that affect ENS development (18,26). The observation that elevated collagen VI levels reduce the speed of ENCDC migration fits well with long-standing observations that extracellular matrix molecules and matrix metalloproteinases influence ENS development (5 Tg /Tg bowels are only about 3-fold higher than those in WT bowels, an observation ascribed to the need to incorporate COL6A4 protein into trimeric collagen monomers that also contain COL6A1 and COL6A2, which are encoded by genes that are not overexpressed in Hol Tg /Tg mice.…”

Section: Discussionmentioning

confidence: 99%

“…Over the past few decades there have been dramatic advances in our understanding of HSCR anatomy, embryology, physiology, and genetics (4,5,18). Early studies by Yntema and Hammond showed that the ENS forms from enteric neural crestderived cells (ENCDCs) that originate primarily in the vagal region of the neural tube (19).…”

Section: O M M E N T a R Ymentioning

confidence: 99%

“…These ENCDCs proliferate vigorously as they colonize fetal bowel in a rostral to caudal progression, pursuing one of the longest migratory routes of any cell population during fetal development ( Figure 1A). ENCDCs then differentiate into diverse neuron and glia subtypes that form a network in the bowel wall with about as many neurons as the spinal cord and every transmitter in the central nervous system (3,18). Despite these advances in our understanding of ENS development, the causal link between trisomy 21 and increased HSCR incidence has remained elusive.…”

Section: Hirschsprung's Disease: Congenital Absence Of Distal Bowel Ementioning

confidence: 99%

“…Up to 10% of children with HSCR have Down syndrome, and 1% to 2% of children with Down syndrome have HSCR. Thus, Down syndrome increases HSCR risk about 50-to 100-fold above the general population risk (~1:5,000) and is a common underlying partially penetrant cause of HSCR (4).Over the past few decades there have been dramatic advances in our understanding of HSCR anatomy, embryology, physiology, and genetics (4,5,18). Early studies by Yntema and Hammond showed that the ENS forms from enteric neural crestderived cells (ENCDCs) that originate primarily in the vagal region of the neural tube (19).…”

mentioning

confidence: 99%

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Hirschsprung’s disease, Down syndrome, and missing heritability: too much collagen slows migration

Heuckeroth¹

2015

Journal of Clinical Investigation

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C o m m e n t a r y4 3 (17), suggesting that one or more genes on chromosome 21 contributes to HSCR etiology. Up to 10% of children with HSCR have Down syndrome, and 1% to 2% of children with Down syndrome have HSCR. Thus, Down syndrome increases HSCR risk about 50-to 100-fold above the general population risk (~1:5,000) and is a common underlying partially penetrant cause of HSCR (4).Over the past few decades there have been dramatic advances in our understanding of HSCR anatomy, embryology, physiology, and genetics (4,5,18). Early studies by Yntema and Hammond showed that the ENS forms from enteric neural crestderived cells (ENCDCs) that originate primarily in the vagal region of the neural tube (19). These ENCDCs proliferate vigorously as they colonize fetal bowel in a rostral to caudal progression, pursuing one of the longest migratory routes of any cell population during fetal development ( Figure 1A). ENCDCs then differentiate into diverse neuron and glia subtypes that form a network in the bowel wall with about as many neurons as the spinal cord and every transmitter in the central nervous system (3, 18). Despite these advances in our understanding of ENS development, the causal link between trisomy 21 and increased HSCR incidence has remained elusive. Analysis of partial trisomy 21 phenotypes suggested that an extra copy of at least one gene in the interval from 33.5 to 46.25 Mb increased HSCR risk (20). This interval contains 122 known genes, including DSCAM, BACE2, COL18A1, and COL6A1. A recent SNP association study suggested that excess DSCAM may be important for HSCR pathogenesis in Down syndrome, but excess DSCAM has not been confirmed experimentally to cause HSCR-like disease in model systems (21). Unbiased approach to identify genes critical for ENS developmentIn this issue, Soret and colleagues took an unbiased, forward genetics approach and used insertional mutagenesis to identify potential regulators of neural crest-derived cell (NCC) migration (22). To simplify the screening process, Soret et al. randomly inserted a tyrosinase (Tyr) minigene, which rescues pigment production in NCCderived melanocytes, into albino FVB/N mice and then evaluated animals with nonuniform pigment patterns. Because melanocytes and the ENS are both neural crest derivatives, some mice with pigmentation defects were also expected to have ENS defects, mimicking the human "neurocristopathy" called Waardenburg-Shah syndrome (Waardenburg syndrome type Hirschsprung's disease (HSCR) causes functional intestinal obstruction due to the absence of the enteric nervous system (ENS) in the distal bowel and is usually diagnosed shortly after birth or during childhood. While several genetic and nongenetic factors have been linked to HSCR, the underlying mechanisms that prevent ENS precursors from colonizing distal bowel during fetal development are not completely understood in many affected children. In this issue of the JCI, Soret and colleagues identify a new mechanism that causes HSCR-like disease in mice and involves deposition o...

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Section: Discussionmentioning

confidence: 99%

Section: O M M E N T a R Ymentioning

confidence: 99%

Section: Hirschsprung's Disease: Congenital Absence Of Distal Bowel Ementioning

confidence: 99%

mentioning

confidence: 99%

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Hirschsprung’s disease, Down syndrome, and missing heritability: too much collagen slows migration

Heuckeroth¹

2015

Journal of Clinical Investigation

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“…These enteric neural crest-derived cells (ENCCs) proliferate, differentiate, and project neurites to appropriate target cells. [85][86][87] Live imaging has contributed to our understanding of 2 important aspects of ENS development: (1) the migration of ENCCs in the gut and (2) the development of neural activity in the immature ENS.…”

Section: Live Imaging Of the Developing Enteric Nervous Systemmentioning

confidence: 99%

Optical Tools to Investigate Cellular Activity in the Intestinal Wall

Boesmans

Hao

Berghe

2015

J Neurogastroenterol Motil

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Live imaging has become an essential tool to investigate the coordinated activity and output of cellular networks. Within the last decade, 2 Nobel prizes have been awarded to recognize innovations in the field of imaging: one for the discovery, use, and optimization of the green fluorescent protein (2008) and the second for the development of super-resolved fluorescence microscopy (2014). New advances in both optogenetics and microscopy now enable researchers to record and manipulate activity from specific populations of cells with better contrast and resolution, at higher speeds, and deeper into live tissues. In this review, we will discuss some of the recent developments in microscope technology and in the synthesis of fluorescent probes, both synthetic and genetically encoded. We focus on how live imaging of cellular physiology has progressed our understanding of the control of gastrointestinal motility, and we discuss the hurdles to overcome in order to apply the novel tools in the field of neurogastroenterology and motility.

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Bi‐Layered Tubular Microfiber Scaffolds as Functional Templates for Engineering Human Intestinal Smooth Muscle Tissue

Chen

Guo

Manousiouthakis

et al. 2020

Adv Funct Materials

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Designing biomimetic scaffolds with in vivo-like microenvironments using biomaterials is an essential component of successful tissue engineering approaches. The intestinal smooth muscle layers exhibit a complex tubular structure consisting of two concentric muscle layers in which the inner circular layer is orthogonally oriented to the outer longitudinal layer. Here, a 3D bi-layered tubular scaffold is presented based on flexible, mechanically robust, and well aligned silk protein microfibers to mimic the native human intestinal smooth muscle structure. The scaffolds are seeded with primary human intestinal smooth muscle cells to replicate intestinal muscle tissues in vitro. Characterization of the tissue constructs reveals good biocompatibility and support for cell alignment and elongation in the different scaffold layers to enhance cell differentiation and functions. Furthermore, the engineered smooth muscle constructs support oriented neurite outgrowth, a requisite step to achieve functional innervation. These results suggest these microfiber scaffolds as functional templates for in vitro regeneration of human intestinal smooth muscle systems. The scaffolding provides a crucial step toward engineering functional human intestinal tissue in vitro, as well as engineering other types of smooth muscles in terms of their similar phenotypes. Such utility may lead to a better understanding of smooth muscle associated diseases and treatments.

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Building a second brain in the bowel

Cited by 116 publications

References 137 publications

Hirschsprung’s disease, Down syndrome, and missing heritability: too much collagen slows migration

Hirschsprung’s disease, Down syndrome, and missing heritability: too much collagen slows migration

Optical Tools to Investigate Cellular Activity in the Intestinal Wall

Bi‐Layered Tubular Microfiber Scaffolds as Functional Templates for Engineering Human Intestinal Smooth Muscle Tissue

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