Neural Circuit Development and Function in the Healthy and Diseased Brain

Comprehensive Developmental Neuroscience

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• Publisher: Academic Press
• Year: 2013
• eBook ISBN: 9780123973467
• Topic: Scienze biologiche
• Subtopic: Neuroscienza

The genetic, molecular, and cellular mechanisms of neural development are essential for understanding evolution and disorders of neural systems. Recent advances in genetic, molecular, and cell biological methods have generated a massive increase in new information, but there is a paucity of comprehensive and up-to-date syntheses, references, and historical perspectives on this important subject. The Comprehensive Developmental Neuroscience series is designed to fill this gap, offering the most thorough coverage of this field on the market today and addressing all aspects of how the nervous system and its components develop. Particular attention is paid to the effects of abnormal development and on new psychiatric/neurological treatments being developed based on our increased understanding of developmental mechanisms. Each volume in the series consists of review style articles that average 15-20pp and feature numerous illustrations and full references. Volume 3 offers 40 high level articles devoted mainly to anatomical and functional development of neural circuits and neural systems, as well as those that address neurodevelopmental disorders in humans and experimental organisms.- Series offers 144 articles for 2904 full color pages addressing ways in which the nervous system and its components develop- Features leading experts in various subfields as Section Editors and article Authors- All articles peer reviewed by Section Editors to ensure accuracy, thoroughness, and scholarship- Volume 3 sections include coverage of: mechanisms that control the assembly of neural circuits in specific regions of the nervous system, multiple aspects of cognitive development, and disorders of the nervous system arising through defects in neural development

III

Diseases

Chapter 27 Neural-Tube Defects

Chapter 28 Fetal Alcohol Spectrum Disorder

Chapter 29 Azetidine-2-Carboxylic Acid and Other Nonprotein Amino Acids in the Pathogenesis of Neurodevelopmental Disorders

Chapter 30 Down Syndrome

Chapter 31 Lissencephalies and Axon Guidance Disorders

Chapter 32 Developmental Disabilities, Autism, and Schizophrenia at a Single Locus

Chapter 33 Fragile X Clinical Features and Neurobiology

Chapter 34 Autisms

Chapter 35 Neurodevelopmental Genomics of Autism, Schizophrenia, and Related Disorders

chapter 36 Excitation–Inhibition Epilepsies

Chapter 37 Sensory Organ Disorders (Retina, Auditory, Olfactory, Gustatory)

Chapter 38 The Developmental Neurobiology of Repetitive Behavior

Chapter 39 Disorders of Cognitive Control

Chapter 40 Language Impairment

Chapter 27

Neural-Tube Defects

C. Pyrgaki¹ and L. Niswander^1,2, ¹University of Colorado Denver, Aurora, CO, USA, ²Howard Hughes Medical Institute, Aurora, CO, USA

Outline

27.1 Neural-Tube Defects

27.1.1 Types of NTDs

27.1.2 Clinical Aspects and Prognosis of NTDs

27.1.3 Etiology of NTDs

27.1.3.1 Genetics of NTDs

27.2 Vertebrate Neurulation

27.2.1 Animal Models for Vertebrate Neurulation Studies

27.2.2 Primary and Secondary Neurulation

27.2.3 Neurulation in Amniote Model Systems

27.2.4 Neurulation in Humans

27.3 Genetic Approaches used to Uncover Regulators of Neural-Tube Closure in Mice

27.4 Molecular Basis of NTDs

27.4.1 Genes Controlling Convergent Extension/PCP Pathway and NTDs

27.4.2 Neural-Tube Patterning

27.4.2.1 Anterior–posterior Patterning Genes and NTDs

27.4.2.2 Dorsal–ventral Patterning Genes and NTDs

27.4.2.3 Bending of the Neural Plate and NTDs

27.4.2.4 NTDs due to Disruption of Neural-fold Fusion

27.4.2.5 NTD due to Disruption of Apoptosis

27.4.2.6 NTD due to Disruption of Proliferation

27.5 Future Directions

References

27.1 Neural-Tube Defects

After heart defects, neural-tube defects (NTDs) are the second most common birth defect, occurring in approximately 300 000 newborns worldwide (~ 1:1000 live births) (Botto et al., 1999). The prevalence of NTDs varies considerably between different racial and ethnic groups (Carmichael et al., 2004; Feldman et al., 1982; Feuchtbaum et al., 1999). In the United States, the two most common types of NTDs, spina bifida and anencephaly, are estimated to affect ~ 3000 pregnancies each year, with caudal NTDs occurring at a higher rate than cranial NTDs (Canfield et al., 2009; CDC, 2004). Both cranial and caudal NTDs can be associated with craniofacial defects (Rittler et al., 2008), but the majority of NTDs are nonsyndromic (Hall et al., 1988). NTDs, especially those of the cranial region, seem to have a higher prevalence among females (Rogers and Morris, 1973; Seller, 1987), although the reason for this sex difference is not well understood.

27.1.1 Types of NTDs

NTDs are divided into two major groups, cranial NTDs and spinal NTDs, and the nomenclature and classification of NTDs in humans are based on position and severity of the NTDs. Cranial NTDs result from failure of the neural tube to close in the cranial region and are classified as follows:

1. Encephalocele, defined as herniation of the cranial vault. Encephalocele can be either a meningocele, if the herniation contains only cerebral spinal fluid (CSF) and meninges, or a meningoencephalocele, if it also contains neural tissue (McComb, 1997).

2. Anencephaly, where the cranial vault is absent and the neural tissue degenerates by week 8 of gestation (Calzolari et al., 2004).

Spinal NTDs also are referred to as spinal dysraphisms. This term was coined by Lichtenstein in 1940 to describe incomplete fusion or malformations of structures in the dorsal midline of the back, particularly congenital abnormalities of the vertebral column and spinal cord (Tavafoghi et al., 1978). These can be further divided into three groups:

1. Spina bifida occulta, which in its strict definition refers only to bone-fusion defects in the spine.

2. Spina bifida cystica, which refers to meningocele and myelomeningocele, where the herniation contains not only CSF, but also neuronal tissue.

3. Spina bifida aperta (SBA), in which the neural tissue is exposed to the environment (Kaufman, 2004).

A relatively rare form of dysraphism that is open or exposed results from the failure of closure of the neural tube throughout its entire length and is called craniorachischisis (Coskun et al., 2009). The term spina bifida has become commonly associated with the open spinal dysraphism of a myelomeningocele.

27.1.2 Clinical Aspects and Prognosis of NTDs

NTDs can be fatal; all exencephalic embryos are stillborn or die shortly after birth, whereas the mortality rate of babies with spina bifida is especially high over the first year of life. Individuals with less severe myelomeningocele suffer from lifelong disabilities, including reduced mobility, little or no bowel and bladder control, and urological infections, and they often require surgical interventions to control the effect of hydrocephalus, the build-up of fluid inside the skull caused by obstruction of CSF circulation (Simeonsson et al., 2002). NTDs pose a considerable monetary burden on the health care system (Kinsman and Doehring, 1996), as well as a significant emotional burden on the affected individual and his/her family. Therefore, understanding neural-tube development and the causes of NTDs are among the most important health-related studies today.

27.1.3 Etiology of NTDs

The etiology of NTDs is complex and involves both genetic and environmental factors, which makes NTDs a classic example of a multifactorial disorder.

27.1.3.1 Genetics of NTDs

The genetic risk of a recurrent NTD in a family with one child with an NTD is 2–5%, a 50-fold increase compared with the rest of the population (Forrester and Merz, 2005). Despite the evidence that genetics plays a pivotal role in the occurrence of NTDs, there are few data on single-gene defects directly associated with NTDs in humans. A number of chromosome rearrangements, such as trisomies 13 and 18, and known genetic syndromes, for example, Meckel syndrome, are associated with NTDs (Lynch, 2005). Chromosomal abnormalities, such as aneuploidy, are present in 5–17% of cases with NTDs (Kennedy et al., 1998), and a 13q deletion, with a critical region at 13q33-34, is strongly correlated with the occurrence of NTDs (Luo et al., 2000). These data can be used to extract clues in an effort to determine the identity of genes involved in neural-tube closure. Clues as to candidate genes for association studies of human NTDs also have been derived from research in animal models of NTD, as described below and as outlined in comprehensive reviews by Harris and Juriloff in 2007 and 2010.

27.1.3.1.1 Environment and NTDs

Maternal diabetes during pregnancy is a key environmental factor, as there is a greater than tenfold increase in NTD frequency in the offspring of diabetic mothers as compared to the general population (Milunsky et al., 1982). The mechanism by which diabetes contributes to failure of neural-tube closure in humans remains unclear. However, a mouse model of diabetes showed a correlation between elevated blood glucose in the mother, increased apoptosis of neural cells, and reduced levels of Pax3, a gene required for neural-tube (NT) formation (Fine et al., 1999; Phelan et al., 1997). Genomics studies show that maternal diabetes can alter transcriptional programs in the developing mouse embryo, potentially affecting genes that directly and indirectly control NT formation (Pavlinkova et al., 2009). Maternal hyperthermia during pregnancy can increase the risk of NTDs up to twofold, although the mechanism responsible for this increase is unknown (Lynberg et al., 1994). Pharmacological agents, among them valproic acid (Nau et al., 1991) and antiepileptic drugs, are associated with an increased incidence of NTDs. For example, antiepileptic drugs can increase NTD risk by 10- to 20-fold (Lindhout et al., 1992). Lifestyle choices such as drinking, smoking, and recreational drugs also increase the risk of NTDs through unknown mechanisms (Suarez et al., 2008). Finally, studies have provided a link between dietary choices and risk for NTDs. In general, vitamin intake is not correlated with reduced risk for NTDs (Carmichael et al., 2003); however, there is one dietary supplement, folic acid, which can reduce the risk for NTDs when added to the maternal diet periconceptionally. Folic acid is the environmental factor that has attracted the most attention from developmental biologists, epidemiologists, and the general public due to the view that it has a protective effect against NTDs (Honein et al., 2001). Epidemiological studies started in the early 1980s showed that maternal folic-acid supplementation led to a significant reduction in NTD incidence (Laurence, 1985). This evidence dramatically influenced public-health policies and led to food-fortification programs in the United States and a number of other countries. The mechanism by which folic acid affects the incidence of NTDs remains largely unknown, despite the investigative efforts of a number of laboratories worldwide concerning its effect on the developing embryo.

As noted, there is a gap in knowledge of the mechanisms that lead to NTDs with respect to both genetic and environmental causes. This lack of knowledge significantly limits efforts of the scientific and medical communities toward the prevention of NTDs, both through genetic counseling and through control of the embryonic environment before and during NT formation.

27.2 Vertebrate Neurulation

27.2.1 Animal Models for Vertebrate Neurulation Studies

Neural-tube development requires the coordination of multiple tissues (neural ectoderm, the neighboring mesenchyme, and the overlying ectoderm) in both space and time. For over 50 years, a number of animal systems have been used to study NT development. Model systems such as birds (Averbuch-Heller et al., 1994; Bel-Vialar et al., 2002; Schoenwolf et al., 1989) and amphibians (Clarke et al., 1991; Davidson and Keller, 1999; Roffers-Agarwal et al., 2008) and zebrafish (Nyholm et al., 2009; Puschel et al., 1992; Sumanas et al., 2005) have contributed considerable insight into neurulation. The mouse is the most extensively studied mammalian experimental model for neurulation and NTD, and it most closely recapitulates human neurulation. However, even mice have limitations as a model of human NT development. For example, there are thought to be differences between mice and humans in the number of closure initiation sites, the sites where the neural folds first meet. Moreover, very few mouse models of NTD are representative of nonsyndromic human NTDs (Juriloff and Harris, 2000). Despite these differences, the mouse undergoes neurulation in a manner that is closer to human than to other animal models used to study neurulation to date. Mo...

Table of contents

• Cover image
• Title page
• Table of Contents
• Copyright
• Editors-in-Chief
• Section Editors
• Contributors
• Introduction to Comprehensive Developmental Neuroscience
• I: Circuit Development
• II: Cognitive Development
• III: Diseases
• Index