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Building a brain in the gut development of the enteric nervous system

Building a brain in the gut development of the enteric nervous system
Building a brain in the gut development of the enteric nervous system

Clin Genet 2013:83:307–316

Printed in Singapore.All rights reserved ?2012John Wiley &Sons A/S.Published by Blackwell Publishing Ltd

CLINICAL GENETICS doi:10.1111/cge.12054

Developmental Biology:Frontiers for Clinical Genetics

Section Editors:

Jacques L.Michaud,e-mail:jacques.michaud@recherche-ste-justine.qc.ca Olivier Pourqui′e ,e-mail:pourquie@igbmc.fr

Building a brain in the gut:development of the enteric nervous system

Goldstein AM,Hofstra RMW,Burns AJ.Building a brain in the gut:development of the enteric nervous system.

Clin Genet 2013:83:307–316.?John Wiley &Sons A/S.Published by Blackwell Publishing Ltd,2012

The enteric nervous system (ENS),the intrinsic innervation of the gastrointestinal tract,is an essential component of the gut

neuromusculature and controls many aspects of gut function,including coordinated muscular peristalsis.The ENS is entirely derived from neural crest cells (NCC)which undergo a number of key processes,including extensive migration into and along the gut,proliferation,and

differentiation into enteric neurons and glia,during embryogenesis and fetal life.These mechanisms are under the molecular control of numerous signaling pathways,transcription factors,neurotrophic factors and

extracellular matrix components.Failure in these processes and consequent abnormal ENS development can result in so-called enteric neuropathies,arguably the best characterized of which is the congenital disorder Hirschsprung disease (HSCR),or aganglionic megacolon.This review focuses on the molecular and genetic factors regulating ENS development from NCC,the clinical genetics of HSCR and its associated syndromes,and recent advances aimed at improving our understanding and treatment of enteric neuropathies.

Con?ict of interest

The authors have no con?ict of interest.

AM Goldstein a ,RMW Hofstra b and AJ Burns b,c

a

Department of Pediatric Surgery,

Massachusetts General Hospital,Harvard Medical School,Boston,MA,USA,b

Department of Clinical Genetics,

Erasmus Medical Center,Rotterdam,The Netherlands,and c Neural Development and Gastroenterology Units,UCL Institute of Child Health,London,UK

Key words:enteric nervous system –Hirschsprung disease –enteric

neuropathies –neural crest cells –RET Corresponding author:Alan J.Burns,Neural Development and

Gastroenterology Units,UCL Institute of Child Health,30Guilford Street,London,WC1N 1EH,UK.Tel.:+442079052721;fax:+442078314366;e-mail:alan.burns@https://www.doczj.com/doc/b49827497.html,

Received 2October 2012,revised and accepted for publication 1November 2012

A functional gastrointestinal (GI)tract is essential for transporting,absorbing,digesting,and excreting food and waste,for protecting the host from ingested pathogens,allergens,and toxins,and for continuously monitoring and responding to the state of the intestinal lumen.The principal conductor of this highly orches-trated symphony is the enteric nervous system (ENS),a vast and complex network of neurons and glial cells that is located along the length of the GI tract and repre-sents an important component of the autonomic nervous system (1).While extrinsic innervation from the cen-tral nervous system can modulate ENS function,the ENS serves as an intrinsic nervous system for the gut,capable of controlling most of the functions of the intes-tine independently.It is because of its complexity and autonomous function that the ENS is often referred to as the ‘second brain’(2).

The ENS contains approximately 100million neu-rons (3)within at least 18functional classes (4).It is organized in two concentric rings of interconnected gan-glia,consisting of both enteric neurons and enteroglial cells,interconnected by interganglionic ?bers (Fig.1).The outer ring is the myenteric (Auerbach’s)plexus,located between the circular and longitudinal muscle layers,and the inner ring is the submucosal (Meiss-ner’s)plexus,which is absent in the esophagus.The

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(a)

(b)

(c)

Fig.1.Schematic showing formation of enteric nervous system(ENS)from neural crest-derived precursors.(a)Vagal neural crest-derived cells enter the proximal(oral)end of the embryonic gut and migrate along its entire length giving rise to the majority of the neurons and glia of the ENS. Sacral neural crest-derived cells enter the hindgut and migrate in an oral direction to form neurons and glia in the distal portion of the gut.(b)In the post-natal gut,the ENS is organized in web-like plexuses that are located between the muscle layers:the myenteric plexus is situated between the longitudinal and circular muscle layers,and the submucosal plexus between the circular muscle and the mucosa.(c)The enteric plexuses contain small groupings of enteric neurons and glia.FG,foregut;MD,midgut;HD,hindgut.

ENS contains many different types of neurons,includ-ing primary afferent neurons that sense chemical or mechanical stimuli in the lumen and then signal via ascending and descending interneurons to excitatory and inhibitory motoneurons that control effector cell function(4).The re?ex circuits produced by these synaptically interconnected neurons are responsible for coordinating the major functions of the ENS,including the regulation of intestinal motility,absorption,secre-tion,and blood?ow.

Congenital and acquired enteric neuropathies can lead to serious health consequences,typically mani-festing with abnormal gut motor function(5,6).For example,in?ammatory enteric neuropathies,which can be caused by paraneoplastic,infectious,or immune-mediated diseases,can lead to gastroparesis,intestinal pseudo-obstruction,or colonic inertia.De?ciencies of selective neurotransmitters have been described in esophageal achalasia and congenital hypertrophic pyloric stenosis,both associated with abnormal intesti-nal sphincter function.Mitochondrial dysfunction can lead to intestinal dysmotility from neuronal cell injury, as in mitochondrial neurogastrointestinal encephalopa-thy.Enteric ganglioneuromas,occurring in multiple endocrine neoplasia type2B,are associated with severe colonic dysmotility(7).

The classic enteric neuropathy is Hirschsprung dis-ease(HSCR),a congenital disease characterized by the absence of enteric ganglia along variable lengths of dis-tal colon(8,9).Congenital aganglionosis,which occurs in1in5000live-births,is limited to the rectosigmoid colon in80%of cases,referred to as short-segment HSCR(S-HSCR),and most commonly presents with the failure of a newborn to pass meconium within 48h of life,often with abdominal distension and vom-iting.A contrast enema X-ray showing narrowing of the distal colorectum with dilation proximally supports the diagnosis of HSCR,and a rectal biopsy reveal-ing the absence of enteric ganglia makes the de?nitive diagnosis.Treatment consists of surgical resection of the aganglionic segment and anastomosis of normally ganglionated bowel to the anus.

This review focuses on the molecular and cellular factors regulating ENS morphogenesis,the clinical genetics of HSCR and its associated syndromes,and recent advances aimed at improving our understanding and treatment of enteric neuropathies.

Development of the ENS

The ENS is entirely derived from the neural crest, a transient structure that arises early in development

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during formation of the neural tube,the precursor of the brain and spinal cord.The progeny of the neural crest,neural crest cells(NCC),migrate extensively throughout the embryo,proliferate,and differentiate into a wide variety of cell types including melanocytes, craniofacial cartilage and bone,neurons and glia of the peripheral and ENS,and smooth muscle(10).Failure in key processes underlying NCC development can result in a number of wide ranging clinically important neural crest disorders(neurocristopathies)that affect pigmentation,alter craniofacial formation,result in deafness,give rise to tumors,or impact the innervation of the gut(i.e.HSCR)(11).

Studies in the1950s and1970s on chick embryos demonstrated that the vagal(hindbrain)region of the neural crest,adjacent to somites1–7,gives rise to the majority of ENS cells along the entire length of the gut.In the last few decades,numerous aspects of ENS development have been extensively studied,with remarkable conservation of cell behavior and molecular control described in species such as?sh,avians,mice and humans.In the mouse,the most widely studied animal model of ENS development,vagal NCC emerge from the neural tube around embryonic day8.5(E8.5), reach the foregut at E9–E9.5(12,13),and migrate rostrocaudally to colonize the entire length of the gut by E13.5–14(14).In the human,this journey by vagal NCC along the gut begins at week4of gestation and is completed by approximately week7(15).In addition to this principal vagal NCC contribution to the gut,a second,more caudal region of the neuraxis,the sacral neural crest,also contributes a smaller number of cells that mainly colonize the terminal region of the mouse and avian hindgut(16,17).Sacral neural crest-derived cells migrate rostrocaudally along the hindgut,opposite to the direction of migration of the vagal neural crest-derived cells.The neuronal subtypes and role(s)of sacral NCC remain unclear,and whether the sacral neural crest contributes to human ENS formation is still unknown.

In order to form a functional ENS along the entire length of the gut,vagal and sacral NCC must undergo a number of key processes including migration,survival, proliferation,neuronal and glial differentiation,and axon formation(Figure1).Numerous transcription fac-tors,signaling pathways,and neurotrophic factors have been shown to be involved in regulating each of these critical processes,a number of which are summarized in Table1,elaborated upon below,and reviewed pre-viously(18,19).These advances in our understanding of ENS development have allowed a number of mark-ers to be used to identify undifferentiated NCC prior to their entry into the gut(termed pre-enteric NCC), including the transcription factors Sox10and Phox2b, the G protein-coupled receptor endothelin receptor B (EdnrB),the low-af?nity nerve growth receptor p75, and the receptor tyrosine kinase Ret(Table1). Enteric NCC(ENCCs),as they are termed upon entering the gut,are undifferentiated at the wavefront of migration and express Sox10,Ret,p75,Phox2b, Ednrb and the transcriptional regulator Mash1.Behind the migratory wavefront,ENCCs are at different stages of maturation,with neuronal differentiation,which begins before glial differentiation,commencing shortly after they invade the foregut.This commitment to the neuronal lineage is associated with downregulation of Sox10and p75,maintenance of Ret and Phox2b expression,and upregulation of pan-neuronal markers, including PGP9.5,neuro?lament,neuronal class IIIβ-tubulin(Tuj1),HuC and HuD.Although committed to a neuronal fate,these cells are still considered to be progenitors as they lack neuron-subtype-speci?c markers(e.g.NOS,VIP,NPY,SubP,ChAT)and remain mitotically active.To commit to the glial lineage,ENCCs maintain Sox10and p75expression, downregulate Ret,and upregulate B-FABP?rst and S100and GFAP later in their differentiation(Table1).

Molecular mechanisms in ENS development

ENS development is a highly dynamic process in which ENCC migration,proliferation,and differentiation all occur simultaneously at different positions along the gut.While most cells at the migratory wavefront con-tinue to proliferate and invade regions lacking ENCCs, those behind the wavefront establish themselves and begin to differentiate into neurons or glia,although some continue to proliferate to?ll gaps created by the growing intestine.Several signaling pathways have essential roles in coordinating these processes and the timing and location of their expression is critical.

Ret and EdnrB signaling:balancing cell proliferation

and differentiation in the ENS

Glial cell-derived neurotrophic factor(GDNF)is expressed in the mesoderm of the embryonic gut and activates a receptor complex on migrating ENCCs. This complex consists of the transmembrane recep-tor tyrosine kinase,Ret,and a co-receptor,Gdnf fam-ily receptorα1(GFRα1)(20).Null mutations of Ret, Gdnf,or GFRα1result in aganglionosis of the small and large intestine(21–24),and GDNF haploinsuf?-ciency leads to severe hypoganglionosis(25)(Table2). At early stages,Ret signaling supports the survival of ENCCs,with its loss leading to signi?cant apop-tosis in the foregut(26).Ret is also strongly mito-genic(27–31),an essential function for expanding the pool of ENCCs so that suf?cient numbers are avail-able to colonize the entire GI tract.The proliferative effect of Gdnf-Ret signaling predominates during early stages when ENCCs are still migrating along the gut (27,31),whereas at later developmental stages,Gdnf-Ret promotes neuronal differentiation(26–28).GDNF is also a potent chemoattractive factor for ENCCs, expressed most highly in the intestinal mesenchyme ahead of the wavefront and thereby possibly drawing them distally down the gut(31–33).A neurotrophic factor closely related to GDNF,neurturin,also activates the Ret receptor.Mouse mutations in this gene result in hypoganglionosis speci?cally affecting the myenteric plexus(34).

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Table1.Molecular markers expressed by NCC and their cellular derivatives at key stages of ENS development in the mouse [modi?ed from(19)].

Stage of

development Key cellular events Cell types Markers expressed by NCC and their progeny

E8.5Delamination from vagal region of

neural tube

Vagal NCCs Sox10/p75

E9.5Invasion of the embryonic foregut

by vagal progenitor cells

Pre-enteric NCCs Sox10/p75±RET/Phox2b

E10.5Rostrocaudal migration of

progenitor cells

Proliferation of progenitor cells

Start of neuronal differentiation ENCCs(progenitor cells)Sox10/p75/RET/Phox2b;EDNRB;

Mash1

Immature neurons RET/Phox2b/PGP9.5/HuC-D/

TuJ1±Mash1/TH

E11.5Rostrocaudal migration of

progenitor cells

Proliferation of progenitor cells

Neuronal differentiation

(appearance of?rst

neurotransmitters)

Start of glial differentiation ENCCs(progenitor cells)Sox10/p75/RET/Phox2b;EDNRB;

Mash1

Immature neurons RET/Phox2b/PGP9.5/HuC-D/

TuJ1±Mash1/TH;±NOS;±Calb Immature glial cells Sox10/p75/B-FABP

E13.5Completion of rostrocaudal

migration of vagal progenitor

cells

Invasion of the embryonic hindgut

and caudo-rostral migration of

sacral progenitor cells

Proliferation of progenitor cells

Neuronal differentiation

Glial differentiation

Sacral NCCs Sox10/p75±RET/Phox2b

ENCCs(progenitor cells)Sox10/p75/RET/Phox2b;EDNRB Immature neurons RET/Phox2b/PGP9.5/HuC-D/

TuJ1±NOS;±Calb;±VIP;±NPY Immature glial cells Sox10/p75/B-FABP

P0(to adult)Proliferation of progenitor cells

Differentiation of mature neuronal

phenotypes

Differentiation of mature glial

phenotype/s

Gangliogenesis

Formation of functional neuronal

circuits(i.e.onset of

co-ordinated intestinal motility)ENCCs(progenitor cells)Sox10/p75±RET/Phox2b

Neurons RET/Phox2b/PGP9.5/HuC-D/

TuJ1±NOS;±Calb;±VIP;

±NPY;±SubP;±CGRP;±5HT;

±ChAT;±Calret

Glial cells Sox10/p75/Phox2b/B-FABP/S100β/

GFAP

E,embryonic day;ENCC,enteric neural crest cells;ENS,enteric nervous system;NCC,neural crest cells.

Another major signaling pathway in ENS devel-opment is endothelin-3(ET3)–EDNRB.ET3is a 21amino acid peptide expressed in the gut meso-derm,while its G protein-coupled receptor,EDNRB, is present on the ENCC.Targeted mutation of either gene in mice,or of the endothelin converting enzyme-1 (ECE-1)that cleaves ET3from its larger precursor, leads to aganglionosis of the distal colon and pigmenta-tion defects due to de?cient melanocytes(35–37).The primary role of EDNRB signaling is to inhibit the dif-ferentiation of ENCCs(28,38,39)and to keep them in a proliferative state(30,39),thereby maintaining a pool of uncommitted progenitors.Whereas these undif-ferentiated ENCCs can continue migrating,once they differentiate into neurons they become post-mitotic and unable to migrate any farther,leading to the distal agan-glionosis seen in ET3and EDNRB mutant animals(40) (Table2).

A critical determinant of normal ENS development is the size of the ENCC population available to colonize the gut.Experimentally reducing the size of the vagal neural crest in avians leads to distal intestinal aganglionosis(41–43).It has been shown that a critical density of cells at the wavefront is necessary to form the cellular strands that drive ENCC migration(44,45).A low ENCC density delays their rate of migration,which may leave the cells unable to colonize a distal environment that has changed by the time they arrive(46,47),thus coupling cell numbers,rate of migration,and maturation of the microenvironment.ENCC proliferation is thus critically important to drive their colonization,as shown by both experimental and mathematical modeling(48,49). Balancing proliferation and differentiation are therefore vital to ENS development.Whereas ET3and GDNF act synergistically to enhance ENCC proliferation(30), they have antagonistic roles with respect to ENCC differentiation and migration,with ET3inhibiting both of these GDNF-mediated processes(28,31,38,39). This coordinated activity is essential,particularly in the cecal region,where GDNF expression is strongest at the stage when ENCCs are arriving there(31,33).

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Building a brain in the gut Table2.Mouse models of intestinal aganglionosis and gut phenotypes in homozygous null and heterozygous mutants

Gene Homozygous phenotype Heterozygous phenotype

Ret AG of small and large intestine(21)Normal(21)

Gdnf AG of small and large intestine(22,23,24)Hypoganglionosis(25)

Gfrα1AG of small and large intestine(107,108)Normal(107)

Et3ls(lethal spotting)Distal colon AG(36)Normal(36)

Ednrb sl(piebald lethal)Distal colon AG(35)Hyperganglionosis in submucosal plexus(109) Ece-1Distal colon AG(37)ND

Sox10Total intestinal AG(50)Distal colon AG(50,51,110)

b1-integrin Distal colon AG(59)ND

Phox2b Total intestinal AG(56)Normal

Mash1AG of esophagus(111)ND

Pax3AG of small and large intestine(55)Normal

Ihh Patchy AG in small and large intestine(112)ND

AG,aganglionosis;ND,not done.

Additional signals involved in ENS formation

Haploinsuf?ciency of Sox10,a SRY-related HMG tran-scription factor expressed by undifferentiated ENCC progenitors,leads to distal colonic aganglionosis in mice(50,51).Sox10supports the survival of ENCC progenitor cells,with its loss leading to NCC apoptosis prior to their arrival in the foregut(52).Acting together with EdnrB,whose enhancer has SOX10-binding sites (53),Sox10also acts by maintaining ENCCs in an undifferentiated state(54).Similar to ET3signaling, Sox10appears to promote maintenance of a pool of progenitor cells for ENS colonization.Sox10has also been implicated in the activation of Ret transcription (55)and may in?uence ENS development via that pathway as well.Mice lacking Phox2B,a transcrip-tion factor expressed by ENCC progenitor cells(56), develop aganglionosis below the stomach,similar to the Ret knockout phenotype(Table2).This may be explained by the?nding that Phox2B is required for Ret expression(56).

NCC migration,survival,and proliferation rely not only on signaling molecules acting on their respective receptors,but also on the interactions between NCC and the extracellular matrix(57).The aganglionic colon of ET3mutant mice is rich in laminin,which promotes enteric neurogenesis and may contribute to the premature differentiation and distal aganglionosis occurring in this model(58).Studies in EDNRB mutant mice suggest that the observed delay in ENCC migration results in ENCCs reaching the colon at a time when it has become non-permissive,possibly due to increased laminin expression in the more mature colon (46).ENCC-speci?c deletion ofβ1integrin,which is expressed by ENCCs and required for their interaction with the extracellular matrix,leads to abnormal cellular adhesion,delayed migration,and distal aganglionosis (59)(Table2).The migratory defect occurs speci?cally in the cecum/proximal hindgut and is thought to be due to a requirement forβ1integrin-mediated interactions between ENCCs with tenascin-C and?bronectin,which are both highly expressed in the mouse cecum when ENCCs arrive there(60).In avians,ENS formation requires the presence of endothelial cells,which ENCCs appear to use as a scaffold to guide their migration via a β1integrin-dependent interaction between ENCCs and the endothelial cell basement membrane(61). Recently,retinoic acid was shown to be required for ENS development,supporting a non-genetic factor as a possible contributor to the pathogenesis of HSCR.Mice depleted of Vitamin A show colorectal aganglionosis due to impaired lamellipodia formation and reduced ENCC migration in response to GDNF(62).

Hirschsprung disease

HSCR and the challenge of colonizing the distal bowel Why the distal end of the colon is particularly susceptible to aganglionosis,as occurs in HSCR,is not entirely clear.Reduction of Ret dosage to one third of normal levels leads to colonic aganglionosis(63). Other mouse models also display aganglionosis limited to the colorectal region,including mice expressing only the Ret51allele(64),Sox10heterozygotes(51), and targeted mutants of the ET3-EdnrB pathway(35, 36).As the majority of ENS colonization occurs rostrocaudally,distal aganglionosis may simply re?ect the distance ENCCs need to migrate to reach the end of the gut.Given the importance of ENCC proliferation for generating an adequate pool of progenitor cells to populate the intestine,inadequate cell numbers could account for the distal aganglionosis.However, conditional inactivation of Ret in late development, after ENS migration has completed,leads to enteric neuronal cell death speci?cally in the colon(63), suggesting that certain aspects of ENCC development may be unique to the distal gut and that other etiologies may account for the HSCR phenotype.

Genes involved in the development of HSCR disease HSCR is considered an inherited disease which can be transmitted in a Mendelian way,both as a dominant trait and as a recessive trait.The majority of cases are probably polygenic/multifactorial with differences

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in sex ratio,with a male predominance in S-HSCR (4:1),incomplete penetrance and variable expression. Associations with a large number of syndromes and congenital malformations have been observed(65). Linkage analyses of multiplex HSCR families revealed that the RET gene,located at10q11.2,is the major risk factor as almost all HSCR families showed linkage with RET(66,67).Coding sequence mutations in RET are responsible for a dominant form of HSCR (with incomplete penetrance)and coding and splice site mutations have been identi?ed in up to50%of familial cases and15–35%of sporadic cases(68). The mutations are scattered throughout the RET-coding sequence,including large and micro-deletions and a variety of point mutations.RET mutations associated with HSCR are believed to cause a loss of function (haploinsuf?ciency)(69–71).However,RET mutations on their own might not result in aganglionosis,as the penetrance of the RET mutations(in general)is72% in males and51%in females.In addition to RET, mutations have been found in11other genes(Table3). Mutations in these genes,namely EDNRB(72),EDN3 (73,74),ECE1(75),GDNF(76,77),NTN(78),SOX10 (79),PHOX2B(80),KIAA1279/KBP(81),ZFHX1B (82,83),TTF-1(84)and NRG1(85),do not account for more than20%of the cases,supporting genetic heterogeneity for this disorder.

Genes involved in syndromic HSCR

Mutations in many of the genes are found in syn-dromic HSCR cases(Table3).Mutations in EDNRB, EDN3and SOX10were identi?ed in a patient with Shah–Waardenburg syndrome(WS4),which is characterized by congenital hearing loss,pigmentary abnormalities of the hair,skin and eyes,and HSCR disease(79,86).Mutations in PHOX2B have been identi?ed in patients with congenital central hypoven-tilation syndrome(CCHS)and HSCR https://www.doczj.com/doc/b49827497.html,HS is a rare disorder characterized by impairment of autonomic control of spontaneous respiration in the absence of other lung or cardiac disease(80).The coexistence of CCHS and HSCR is known as Haddad syndrome.Mutations in ZFHX1B have been identi-?ed in patients with Mowat–Wilson syndrome,an autosomal dominant disorder characterized by men-tal retardation,epilepsy,delayed motor development, and HSCR disease(82).Mutations in KIAA1279[now called kinesin-binding protein(KBP)]have been iden-ti?ed in patients with Goldberg–Shprintzen syndrome, a rare autosomal recessive disorder characterized by HSCR,microcephaly,mental retardation,and polymi-crogyria(81).A mutation in ECE1was identi?ed in a single patient with craniofacial and cardiac defects(75). Finally,speci?c mutations in RET have been found in patients with HSCR in combination with the cancer syn-drome multiple endocrine neoplasia type2A(MEN2A) or familial medullary thyroid carcinoma(FMTC)(87). Besides mutations in these genes,chromosomal abnormalities are observed in12%of all syndromic HSCR cases.Trisomy21(Down syndrome),which occurs in up to10%of children with HSCR,is the most frequent,accounting for>90%of all known chromosomal defects associated with this disease(65).

Non-coding RET variants

As mentioned above,RET-coding mutations have been identi?ed in50%of familial cases.However,regardless of the RET-coding mutation status,almost all familial cases are linked to the RET locus(66,88).This suggests that non-coding RET mutations must play a major role in the remaining cases.This idea was corroborated in association studies on sporadic(simplex)cases with and without RET-coding mutations,performed on several Caucasian populations and an Asian population.These studies revealed a strong association between a certain haplotype(covering27kb in total)and the disease.This haplotype starts4kb upstream of the RET transcription start site,going all the way to the beginning of exon 2.This haplotype is present in56–62%of patients,but only20%of controls,in the Caucasian population.In the Chinese patient population,the frequency of this haplotype was85%,and40%in controls.This?nding might partially explain the higher incidence of HSCR in Asians compared to Caucasians.Several groups have

Table3.Hirschsprung disease associated genes and their clinical features(modi?ed from(99))

Gene symbol Position Inheritance Phenotype

RET10q11.2Dominant,incomplete penetrance Non-syndromic/MEN2A GDNF5p13Non-Mendelian Non-syndromic

NTN19p13Non-Mendelian Non-syndromic

EDNRB13q22Recessive Dominant(de novo in80%)Shah–Waardenburg Non-syndromic EDN320q13Recessive Dominant,incomplete penetrance Shah–Waardenburg Non-syndromic PHOX2B4p12Dominant(de novo in90%)Haddad syndrome(CCHS) SOX1022q13Dominant(de novo in75%)Shah–Waardenburg

ECE11p36Dominant(de novo)Congenital heart formation ZFHX1B(SIP1)2q22Dominant(de novo)Mowat–Wilson

KIA1279(KBP)10q22.1Recessive Goldberg–Shprintzen

TTF1(TITF1)14q13–Non-syndromic

NRG18p21–Non-syndromic

CCHS,congenital central hypoventilation syndrome.

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focused their studies on?ne-mapping the associated region to identify the location of the causative variant (84,89–96).

Susceptible HSCR loci

Investigators are actively searching for additional susceptibility loci,with or without an associated RET mutation.Linkage studies on multiplex HSCR families identi?ed a new locus at9q31in families linked to RET but without a RET-coding mutation(88).Sibpair

analysis in nuclear families with S-HSCR resulted in signi?cant allele sharing with markers on10q11(RET), and two new loci on19q12and on3p21,respectively (66).A genome-wide scan on43Mennonite trios, all belonging to the same large kindred,resulted in three loci,two of which were known loci(13q22.3-q31.1,EDNRB;10q11.21,RET)and one new locus on 16q23.3(97).Studying a large multigenerational Dutch family with an isolated HSCR phenotype resulted in the identi?cation of a new susceptibility locus on4q31-32(98).Finally,a genome-wide association study on Chinese patients identi?ed NRG1as a susceptibility locus for HSCR(85).

Genetic testing for HSCR–what and who to test?

Current knowledge on the genetic background of HSCR has brought forward,for the patient,several important new insights.The most signi?cant is perhaps the fact that a few percent(up to3%)of non-syndromic HSCR patients have a RET mutation that predisposes them not only for HSCR but also for the cancer syndrome MEN2A or FMTC.As the detection of such a RET mutation has profound clinical consequences for the patients and his or her family it is recommended that all non-syndromic HSCR patients are screened for these speci?c mutations(87,99).This testing should only be offered in combination with genetic counseling.Genetic counseling is also recommended in all syndromic HSCR cases.Depending on the disease phenotype one could decide to screen for speci?c gene(s).Another reason for molecular testing of RET could be to give more accurate estimates for recurrence risks to parents of a non-syndromic HSCR patient.For instance,the ?nding of a pathogenic RET mutation in a male proband with L-HSCR and the exclusion of this mutation in the parents may allow lowering of the recurrence risk of13–17%to less than1%,taking into account the theoretical possibility of a mosaic germ line mutation in one of the parents(100).

Future directions

Better understanding of,and therapies for,congenital diseases affecting the ENS

After over two decades of intense investigations,our understanding of the developmental biology,genetics and etiology of HSCR has signi?cantly advanced.How-ever,the de?ning characteristics of a number of other

* e.g. hypoganglionosis, neuronal intranuclear inclusion disease, ganglionitis, degenerative neuropathy, diffuse ganglioneuromatosis, neuronal dysplasia.

See reference 6.

Fig.2.Flow diagram showing potential experimental approaches for gaining insight to the molecular mechanisms underlying enteric neuropathies,and development of novel therapies for their treatment. enteric neuropathies are still lacking(101,102).This

is partly due to the relatively rare incidence of these diseases,the lack of well de?ned neuropathological features,and the scarcity of animal models in which speci?c gut motility defects can be investigated.Future work may be directed towards:(i)identifying pheno-type/genotype associations within well-de?ned patient groupings(which may require the establishment of international consortia to accumulate a‘critical mass’of patients and tissues for analysis);(ii)utilizing evolv-ing genetic technologies to identify candidate genes for enteric neuropathies;(iii)using animal models including zebra?sh and mice to investigate potential mechanisms underlying enteric neuropathies,including aberrant development of neuronal subtypes,inappro-priate neuronal wiring and network formation,and (iv)developing novel therapies for congenital diseases affecting the ENS(Fig.2).

For this latter point,although gut motility disorders represent relatively rare but clinically challenging conditions with little in the way of de?nitive cures, a number of groups worldwide are currently focusing on the possibility of utilizing stem cells to replace or restore missing or defective ENS cells,particularly with therapy for HSCR in mind.Typical investigative approaches include isolation and propagation of stem cells from various sources(including the gut or CNS,as

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well as iPS and embryonic stem cells),transplantation of stem cells into mouse or other models of gut aganglionosis,and assessment of gut function following transplantation(for reviews see(103–106)).The next challenges in this?eld will be to progress from animal models to the isolation and characterization of stem cells from human sources,and move to‘?rst in man’studies whereby stem cell delivery methods,safety and ef?cacy can be assessed.With these steps in mind, advances in the understanding and treatment of ENS disorders will continue to advance at a rapid pace.

Acknowledgement

A.M.G.is supported by NIH R01DK080914.

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考研真题及答案解析

徐之明权威解析2013年考研政治试题马原客观题答案解析 一、单项选择题马原部分 1.有一副对联,上联是“桔子洲,洲旁舟,舟行洲不行”,下联是“天心阁,阁中鸽,鸽飞阁不飞”。这形象地说明了运动和静止是相互联系的。静止是() A.运动的普遍状态 B.运动的内在原因 C.运动的衡量尺度 D.运动的存在方式 【答案】C 【思路剖析】本题属于案例型考题,即通过一个具体的事例,去探究其中所包含的哲理。题干所引对联的作者,是毛泽东和周恩来。1960年5月,毛泽东、周恩来一行视察长沙,工作之余,到江边散步。遥望橘子洲头,百舸争流,万帆竞发,毛泽东逸兴遄飞,口占一上联:“橘子洲,洲旁舟,舟行洲不行”,此联动静相对,意境悠远,三个断句,两处“顶针”,“洲”和“舟”又是谐音,应对难度极大。毛泽东对身边的周恩来说:“恩来,我一时江郎才尽,请你来个锦上添花如何?”周恩来才思敏捷,了解长沙,应声对道:“天心阁,阁中鸽,鸽飞阁不飞。”天心阁系长沙市内一景,与橘子洲相对。整个对联工整流畅、浑然一体,留下一段佳句和佳话。从考试答题的角度论,最关键的是抓住题干中的最后一句:“这形象地说明了运动和静止是相互联系的。静止是()。“.运动的普遍状态”是胡编的干扰项,学术上没有这个说法。故A.项错误。“.运动的内在原因”是矛盾,故B项为错误。物质的存在方式是运动;没有“运动的存在方式”这个说法。C. 项“静止是运动的衡量尺度”是正确的说法。该说法的出处是马克思、恩格斯的话:“运动应当从它的反面即从静止找到它的量度”。所包含的深层哲理是在对立中认识同一。 【必背考点】《马原》第2章之“运动和静止”。 【应试对策】本题的难度,主要不是来自考查的内容,而是来自于干扰项的设定。“运动”、“普遍”、“内在原因”、“存在方式”等,都是我们学习哲学中经常碰到的基本概念。如果没有理解作为支撑,并且采取临时抱佛脚的突击记忆方式,比较难做出正确的决断。 2.一位机械工程专家讲过这样一件事:“文革”中,他在某地劳动,有一天公社派他去割羊草。他没养过羊,怎么认得羊草呢?但终于一个办法出来了。他把羊牵出去,看羊吃什么就割什么。不到半天就割回了羊草。这位专家之所以这样做是因为他认识到,“羊吃草”与“割羊草”两者之间存在着() A.因果联系 B.必然联系 C.主观联系 D.本质联系 【答案】B 【思路剖析】本题是案例型考题。通过一个生活中的故事,考查所其中所包含的哲理。题干中的“羊吃草”是指羊的行为;“割羊草”是指人的行为。连起来看,

马原知识点整理

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追梦路上有过迷茫 ——华中师大心理学考研记(初试篇) 写着写着发现稍有点偏题,却也是我的本心写照。 先自我介绍 楼主求学路上磕磕绊绊,大四也准备过考研,后来因为实习就放弃了,毕业后一直对读研念念不忘,15年暑假开始全职跨考心理学研究生。初试三百五十多,今天上午终于看到拟录取名单有我的名字,也算初战告捷吧。 其次,对我即将就读的华中师大心理学做个介绍吧! 华师最为大家熟悉的可能就是咨询方向的江光荣老师了,华师咨询室设计很人性化、非常优美,江老师的理论与实践水平都很高。管理方向大牛是马红宇老师,还有一个特聘教授洪建中老师。发展方向的周宗奎老师、教育方向的刘华山老师、社会方向的佐斌老师、人格方向的郭永玉老师、脑认知方向的周治金老师在各自领域都是执牛耳的人物之一。 华师心理学的最大特色是对网络心理学的研究,周宗奎院长领导建立的青少年网络心理与行为教育部重点实验室几乎整合了华师心理学院所有师资,研究方向包括网络认知学习与教学、网络社会行为、网络与青少年心理健康、青少年网络文化与内容安全等。听说华师心理学院每年都会有很多师兄师姐去游戏开发公司、网络产品开发公司任职。是不是很羡慕?那就选择华师吧!爱在华师,今后三年就要在华师学习了,想想就有点小激动。下面对我的考研做个总结,也算是对学弟学妹的一份经验之谈吧。 一、择校 一定要充分搜集资料——各种——包括学校的优势和劣势、导师的研究情况、往年的报录比、各科最低分数线(注意!对绝大部分同学,国家线意义不大)等等等等。这些在学院官方网站大部分都能找到。除此之外,可以多问你有意学校的学长学姐,这个就可以发挥论坛和群的强大功能了。 择校时要考虑的几点: 1.读研的目的。 为了就业?做研究?提高学历?。。。。。。就业选城市和学校,研究选学校与专业,为了学历那就无所谓了。 2.本身实力。 自己可能的努力程度?这是最重要的。好像除了这一点外也没其他的了。自己好好掂量,是否愿意放弃之前去的一系列荣誉?是否能禁得住同学、工作、娱乐的诱惑?家里和学校是否支持。。。。。。说白了,考研就是一场努力了就会有收获的抗战。 3.目标院校相关情况。 学校的实力,该校该学科的实力,该学科各方向的研究情况。特别重要的是报考难度如何。除非抱着非某名校或名师不去的心态,还是要多考虑录取成功率。 4.选择学校一定要有层次,多选几个备胎。 我当时理想的是几所985,根据实际情况选择了华中师大(211),选了母校(一个地方重本)作为备胎。这样复习的时候不会太心慌或太放松,要记住适中的目标动机最有利

【马原】重要知识点整理

马克思主义基本原理 第一章 1、哲学的基本问题 其一,意识和物质、思维和存在,究竟谁是世界的本原,即物质和精神何者是第一性、何者是第二性问题;其二。“我们关于我们周围世界的思想对这个世界本身的关系是怎样的?我们的思维能不能认识现实世界?我们能不能在我们关于现实世界的表象和概念中正确地反映现实?”即思维能否认识或正确认识存在的问题。 2、社会的物质性表现 第一,人类社会依赖于自然界,是整个物质世界的组成部分。 第二,人们谋取物质生活资料的实践活动虽然有意识作指导,但仍然是以物质力量改造物质力量的活动,仍然是物质性的活动。 第三,物质资料的生产方式是人类社会存在和发展的基础,集中体现着人类社会的物质性。综上所述,包括自然界和人类社会在内的整个世界,其真正统一性在于它的物质性。物质是世界的本原,社会运动也是物质运动的一种特殊形式。 3、社会生活的实践性表现 第一,实践是社会关系形成的基础。 第二,实践形成了社会生活的基本领域 第三。实践构成了社会发展的动力 4、矛盾的普遍性与特殊性的辩证关系 第一、盾的普遍性,是指矛盾是自然、社会以及人类思维中客观的普遍的现象;是指矛盾的共性、绝对性。 第二、矛盾的特殊性是指具体事物的矛盾以及矛盾的每一个侧面都有自己的特点;是指矛盾的个性、相对性。 第三、矛盾的普遍性和特殊性的关系是共性与个性的对立统一关系。 第四、矛盾的普遍性即共性是无条件的、绝对的,特殊性即个性是有条件的、相对的;共性包括的是个性中本质的东西,它比个性深刻,个性比共性丰富。 第五、二者相互依存,相互制约:共性寓于(存在于)个性之中,共性只能通过个性而存在;共性统摄着个性,个性总是与共性相联系而存在。割裂了这种联系,就会导致类似“白马非马”的诡辩命题。 第六、二者在一定条件下相互转化:随事物的发展和条件的改变,共性与个性可以相互过渡,相互转化。 5、量变和质变的辩证关系 第一,量变是质变的必要准备 第二,质变是量变的必然结果 第三,量变和质变是相互渗透的 质量互变规律体现了事物发展的渐进性和飞跃性的统一 6、客观规律性与主观能动性的辩证关系 尊重客观规律是发挥主观能动性的前提 在尊重客观规律的基础上充分发挥主观能动性 必须尊重客观规律。发挥人的主观能动性必须以承认规律的客观性为前提。

考研政治攻略

一、对政治这门科目的整体看法 作为一门考研公共课,相比于英语或者数学或者其他专业课,政治算是性价比很高的一门课。考过的人应该都知道,英语这门课的提高是很难的,因为这门课要求有一定的基础,而这种基础不是短时间内能够打好的,更多的在于平时的积累,至于数学,则是一门考察范围比较广、同时有一定深度的学科,这两门课的复习是要花长时间和高强度的。 相比较而言,政治则是一门相对较为轻松的,原因一是作为祖国的大好青年,在20多年中国共产党和社会主义理论教育的成长过程中,我们或多或少都有一点政治见解,同时政治这门课的特点,是和文字打交道,作为一个从小就学习语文的中国人都有一定的理解能力和文字表达能力。出于这个原因,可能很多同学就想:既然是这样,那我干脆不用管这门课吧,反正到时考场凭借自己的措辞和语言组织能力也能考到五六十分吧。这种看法我们非常不赞成的,虽然从论坛上看到一些同学发帖说自己裸考考到60多分甚至70多分,但是您想想,这个概率有多大呢?另外想必是那些考的分数还行的才会到论坛上发帖子吧,更多的是不是充当了炮灰呢?这个是不言而喻的。相反如果话较少的时间得到高分,这是多么惬意的一件事! 所以我和几位斑竹或者其他一些高分同学的观点都是:政治还是要按部就班的来复习,不要抱着裸考和投机的心态,尽量把目标定的高一点,因为目标越高,动力越足。另外一点就是,对于这门课你可以花较少的时间,但分值上却可以上涨二三十分,何乐而不为呢?因为从往年的考生来看,这些考生也都没有把重点花在政治上面,而是花了相对于其他科目比较少的时间来进行政治的复习,最后也都取得了高分,这实在是一门让人很期待的学科啊! 需要提的是,最近在政治版块常常发现同学说自己是理工科的,说自己没有一点政治基础,所以很担心,很迷茫怎样去复习。对于这个问题,想回答的是:第一,政治这么科目和学文学理没有很大关系,当然学文科的有基础的不可否认,但事实上年年都会发现很多理工科政治高分的,这个还是在于自己的复习,对自己多点自信,第二,理工科的不要因为毫无政治基础而放弃这门课,因为适当的给一点时间给政治效果会很好。 二、考研政治之辅导班 每年对这个问题纠结的同学都比较多,特别是新的考生,这其实是一个见仁见智的问题。据我观察,有参加辅导班获得高分的考生,也有报了辅导班但分不高的同学,而未参加辅导班考到高分的也有一部分比例,可以说报不报班影响不是特别大,关键还是个人的复习方法和思路。 这是考研论坛的版友关于是否报辅导班的一个投票:

马原知识点详细版

题型分布,我们是30个1分的单选题,10个2分的多选题,4个5分的简答题,4个5分的辨析题, 1个10分的论述题。标头没有加黑的基本上就是选择题, 绪论(不是很重点,放到考试前记吧) 1、什么是马克思主义? P2:马克思是无产阶级思想的科学体系,从它的创造者、继承者的认识成果讲,马克思主义是…;从 它的阶级属性讲,马克思主义是…;从它的研究对象和主要内容讲… 2、马克思主义体系的组成部分 马克思主义哲学、马克思主义政治经济学、科学社会主义 3、马克思主义产生的历史必然性(马克思主义是时代的产物) 首先,资本主义经济的发展为马克思主义的产生提供了经济、社会历史条件。 其次,无产阶级反对资产阶级的斗争日趋激化,对科学理论的指导提出了强烈的需求。 3、马克思主义的来源及代表人物(名字太长了,我只取了容易记得部分,反正是选择题) 德国古典哲学:黑格尔、费尔巴哈 英国古典政治经济学:亚当·斯密、大卫·李嘉图 法国、英国空想社会主义:圣西门(法国)、傅里叶(法国)、罗伯特·欧文(英国) 4、马克思主义是科学性和革命性的统一 P14 ①辩证唯物主义和历史唯物主义,是马克思主义最根本的世界观和方法论 ②致力于实现以劳动人民为主体的最广大人民的根本利益,是马克思主义最鲜明的政治立场(P16 第 一句话可以出选择题) ③坚持一切从实际出发,理论联系实际,事实求是,在实践中检验真理和发展真理,是马克思主义最 重要的理论品质(选择题中选项一般说是与时俱进) ④实现物质财富极大丰富、人民精神境界极大提高、每个人自由而全面发展的共产社会主义社会,是 马克思主义最崇高的社会理想 5、如何学习马克思主义? 1、学习理论,武装头脑 2、坚持和弘扬理论联系实际的学风,是学习马克思主义基本原理的根本方法 3、用科学的态度对待马克思主义 6、如何运用马克思主义?(把马克思主义作为行动的指南)P22、23中的第一、二、三 第一章世界的物质性及其发展规律 1、哲学的基本问题(即意识与存在的关系问题)P28 哲学基本问题包括两个方面的内容:其一,意识和物质、精神和自然界,究竟谁是世界的本源,既物质和精神何者是第一性、何者是第二性的问题;其二,思维能否认识或正确认识存在的问题。 哲学基本问题是人们在认识世界和改造世界的活动中经常遇到的问题。 2、哲学的类型P29 唯物主义和唯心主义;可知论和不可知论;有神论和无神论;辩证法和形而上学 唯物主义包括:古代朴素唯物主义、近代形而上学唯物主义、现代辩证唯物主义 唯心主义包括:主观唯心主义、客观唯心主义 2、物质的定义{马克思主义哲学物质范畴的理解} P30 第14行,列宁对物质概念作的规定 物质的唯一特性:客观实在性 3、意识的定义P30、31 意识是物质世界长期发展的产物,是人脑的机能和属性,是物质世界的主观映像。意识既是自然世界长期发展的产物,也是社会历史的产物。意识在内容上是客观的,在形式上是主观的。 4、马克思主义的物质观具有丰富而深刻的理论意义P31

考研政治马原知识点解析资本的分类

考研政治马原知识点解析:资本的分类 政治经济学在考研中考察一般为选择题,通常为5-6分,拿下这几分就需要同学们掌握好经济学中的术语,做到不混淆、灵活运行。下面勤思为同学们区分一下不变资本、可变资本、固定资本、流动资本这几个概念,希望同学们在今后的复习中可以思路更加清晰: 一、不变资本与可变资本 1.概念:根据资本在剩余价值生产过程中的作用不同,资本可分为不变资本和可变资本。以生产资料形态存在的资本,在生产过程中只转移自己的物质形态而不改变自己的价值量,不发生价值增值的资本叫做不变资本;可变资本是用来购买劳动力的那部分资本,在生产过程中不是被转移到新产品中去,而是由工人的劳动再生产出来。 2.区分:根据其概念,我们知道区分不变资本与可变资本的标准在于在生产过程中是否能够引起商品价值量的变化。不变资本是以生产资料形态存在的资本,它对应劳动二重性中的具体劳动,工人的具体劳动使其转移到新产品中;可变资本是在资本中能引起商品价值量增加的部分,也即是剩余价值生产过程中的资本,其对应的是抽象劳动,是资本家购买劳动力的那部分资本。具体说来,在资本主义生产过程中,不变资本包括厂房、机器设备、原材料和燃料等这些在生产中不可能增加商品的价值;可变资本即是能使价值增殖的生产要素——资本家付给工人的工资。 二、固定资本与流动资本

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