Hydrocephalus and Hirschsprung’s disease with a mutation of L1CAM

Okamoto, Nobuhiko; Maestro, Rolando Del; Valero, Rebeca; Monrós, Eugènia; Póo, Pilar; Kanemura, Yonehiro; Yamasaki, Mami

doi:10.1007/s10038-004-0153-4

Cited by 65 publications

(41 citation statements)

References 15 publications

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“…Experimental support for this hypothesis comes from mutations in L1 cell adhesion molecule (L1CAM), a protein that maintains such cell–cell contacts. L1CAM mutations reduce ENCC contact and lead to HSCR [65,66]. Since ENCCs at low density migrate more slowly, this may result in those wavefront cells being unable to colonize a microenvironment that is no longer permissive by the time they arrive [67].…”

Section: Molecular and Cellular Control Of Ens Developmentmentioning

confidence: 99%

Enteric nervous system development: A crest cell’s journey from neural tube to colon

Nagy

Goldstein

2017

Seminars in Cell & Developmental Biology

185

134

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The enteric nervous system (ENS) is comprised of a network of neurons and glial cells that are responsible for coordinating many aspects of gastrointestinal (GI) function. These cells arise from the neural crest, migrate to the gut, and then continue their journey to colonize the entire length of the GI tract. Our understanding of the molecular and cellular events that regulate these processes has advanced significantly over the past several decades, in large part facilitated by the use of rodents, avians, and zebrafish as model systems to dissect the signals and pathways involved. These studies have highlighted the highly dynamic nature of ENS development and the importance of carefully balancing migration, proliferation, and differentiation of enteric neural crest-derived cells (ENCCs). Proliferation, in particular, is critically important as it drives cell density and speed of migration, both of which are important for ensuring complete colonization of the gut. However, proliferation must be tempered by differentiation among cells that have reached their final destination and are ready to send axonal extensions, connect to effector cells, and begin to produce neurotransmitters or other signals. Abnormalities in the normal processes guiding ENCC development can lead to failure of ENS formation, as occurs in Hirschsprung disease, in which the distal intestine remains aganglionic. This review summarizes our current understanding of the factors involved in early development of the ENS and discusses areas in need of further investigation.

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Section: Molecular and Cellular Control Of Ens Developmentmentioning

confidence: 99%

Enteric nervous system development: A crest cell’s journey from neural tube to colon

Nagy

Goldstein

2017

Seminars in Cell & Developmental Biology

185

134

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“…The L1 cell adhesion molecule is a membrane glycoprotein belonging to a large class of immunoglobulin superfamily cell adhesion molecules (CAMs) that mediate cell-to-cell adhesion at the cell surface. The L1CAM protein is found primarily in the nervous system and is important in neuronal adhesion, migration, neurite outgrowth, and myelination [4]. Mutations in the L1CAM gene cause neurological abnormalities of variable severity, including congenital hydrocephalus, agenesis of the corpus callosum, spastic paraplegia, bilaterally adducted thumbs, aphasia, and mental retardation (see OMIM).…”

Section: Discussionmentioning

confidence: 99%

“…In contrast, none of the remaining genes encompassed by the rearrangement, such as IRAK1 or IDH3G have been previously related to HSCR. All the L1CAM mutational events reported so far to be responsible for the manifestation of the corresponding clinical pictures, are point sequence changes [4,6,8,10,11] or small deletions [5,9], whose proposed pathogenic mechanisms lead to the suspicion that decreased L1CAM may be a modifying factor in the development of HSCR [4]. It would be licit to speculate that also an increase in the amount of L1CAM, due to a duplication in the dosage of this gene, might be involved someway in the pathogenesis of Hirschsprung in this particular patient.…”

Section: Discussionmentioning

confidence: 99%

“…Among those HSCR-associated syndromes, there exist some clinical presentations with central nervous system anomalies, including the HSAS/MASA spectrum (OMIM 307000 and 303350) ascribed to mutations in the X-linked L1CAM gene [1,4]. Indeed, until now mutations of the L1CAM gene (OMIM 308840) have been found in nine out of ten patients reported to show association of X-linked hydrocephalus with HSCR [4-10]. In addition, two cases with both acrocallosal syndrome and HSCR have been also linked to L1CAM mutations [11].…”

Section: Introductionmentioning

confidence: 99%

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Novel association of severe neonatal encephalopathy and Hirschsprung disease in a male with a duplication at the Xq28 region

et al. 2010

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BackgroundHirschsprung disease (HSCR) is a neurocristopathy characterized by the absence of parasympathetic intrinsic ganglion cells in the submucosal and myenteric plexuses along a variable portion of the intestinal tract. In approximately 18% of the cases HSCR also presents with multiple congenital anomalies including recognized syndromes.MethodsA combination of MLPA and microarray data analysis have been undertaken to refine a duplication at the Xq28 region.ResultsIn this study we present a new clinical association of severe neonatal encephalopathy (Lubs syndrome) and HSCR, in a male patient carrying a duplication at the Xq28 region which encompasses the MECP2 and L1CAM genes.ConclusionsWhile the encephalopathy has been traditionally attributed to the MECP2 gene duplication in patients with Lubs syndrome, here we propose that the enteric phenotype in our patient might be due to the dosage variation of the L1CAM protein, together with additional molecular events not identified yet. This would be in agreement with the hypothesis previously forwarded that mutations in L1CAM may be involved in HSCR development in association with a predisposing genetic background.

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“…L1CAM (termed Ng-CAM in Aves) is related to NCAM, and the gene is mutated in some Hirschsprung patients with X-linked hydrocephalus (Okamoto et al, 2004), and it acts as a modifier for Hirschsprung-associated genes like Sox10 , ednrb and edn3 (Wallace and Anderson, 2011). L1CAM is expressed transiently by early migrating ENC (Anderson et al, 2006; Hackett-Jones et al, 2011; Nagy et al, 2012; Thiery et al, 1985) and later reappears during ENS neuron differentiation and axon extension (Turner et al, 2009).…”

Section: Colonization Of the Gastrointestinal Tract By Enteric Neuralmentioning

confidence: 99%

Simple rules for a “simple” nervous system? Molecular and biomathematical approaches to enteric nervous system formation and malformation

Newgreen¹,

Dufour²,

Howard³

et al. 2013

Developmental Biology

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We review morphogenesis of the enteric nervous system from migratory neural crest cells, and defects of this process such as Hirschsprung disease, centering on cell motility and assembly, and cell adhesion and extracellular matrix molecules, along with cell proliferation and growth factors. We then review continuum and agent-based (cellular automata) models with rules of cell movement and logistical proliferation. Both movement and proliferation at the individual cell level are modeled with stochastic components from which stereotyped outcomes emerge at the population level. These models reproduced the wave-like colonization of the intestine by enteric neural crest cells, and several new properties emerged, such as colonization by frontal expansion, which were later confirmed biologically. These models predict a surprising level of clonal heterogeneity both in terms of number and distribution of daughter cells. Biologically, migrating cells form stable chains made up of unstable cells, but this is not seen in the initial model. We outline additional rules for cell differentiation into neurons, axon extension, cell-axon and cell-cell adhesions, chemotaxis and repulsion which can reproduce chain migration. After the migration stage, the cells rearrange as a network of ganglia. Changes in cell adhesion molecules parallel this, and we describe additional rules based on Steinberg's Differential Adhesion Hypothesis, reflecting changing levels of adhesion in neural crest cells and neurons. This was able to reproduce enteric ganglionation in a model. Mouse mutants with disturbances of enteric nervous system morphogenesis are discussed, and these suggest future refinement of the models. The modeling suggests a relatively simple set of cell behavioral rules could account for complex patterns of morphogenesis. The model has allowed the proposal that Hirschsprung disease is mostly an enteric neural crest cell proliferation defect, not a defect of cell migration. In addition, the model suggests an explanations for zonal and skip segment variants of Hirschsprung disease, and also gives a novel stochastic explanation for the observed discordancy of Hirschsprung disease in identical twins.

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Hydrocephalus and Hirschsprung’s disease with a mutation of L1CAM

Cited by 65 publications

References 15 publications

Enteric nervous system development: A crest cell’s journey from neural tube to colon

Enteric nervous system development: A crest cell’s journey from neural tube to colon

Novel association of severe neonatal encephalopathy and Hirschsprung disease in a male with a duplication at the Xq28 region

Simple rules for a “simple” nervous system? Molecular and biomathematical approaches to enteric nervous system formation and malformation

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