Question

The three forms of open neural tube defect are anencephaly,
craniorachischisis and spina bifida. Explain the embryological origin of
these disorders, with reference to the morphological events that occur
during normal mammalian neural tube closure. In your answer describe
what is known of the causes of these disorders, at the cellular and
molecular level? (500words)

Answer 1

Answer a) Anencephaly, craniorachischisis and spina bifida.

Primary Neurulation: Subtypes of NTDs Relate to Stages of Closure

In the prospective brain and most of the spinal cord, neural tube formation essentially involves the bending of the neuroepithelium at the midline to generate neural folds that elevate, meet, and fuse in the dorsal midline (primary neurulation). Rather than simultaneously rolling up along the extent of the rostrocaudal axis, neural tube closure is discontinuous with distinct sites of initiation located at characteristic axial levels. Moreover, the morphological and molecular requirements for closure vary along the body axis, such that an individual NTD usually affects only a portion of the neural tube. NTDs can thus be attributed to failure of particular initiation events or disruption of the progression of closure between these sites.

In mice, closure is first achieved on embryonic day 8.5 at the level of the hindbrain/cervical boundary (closure 1) (Figure 1a), and failure of this event leads to craniorachischisis. Closure initiates at a second site on embryonic day 9, closure 2, in the caudal forebrain or forebrain/midbrain boundary. Once initial contact and fusion have been established between the tips of the neural folds, closure spreads bidirectionally from the sites of closures 1 and 2 and in a caudal direction from the rostral end of the neural tube (closure 3). The open regions of neural folds, termed neuropores, gradually shorten, leading to complete closure of the anterior neuropore (between closures 2 and 3) on embryonic day 9 and the hindbrain neuropore (between closures 1 and 2) a few hours later. Cranial NTDs (anencephaly) result from failure of closure 2, or incomplete “zippering” between closures 1 and 2, which closes the midbrain and hindbrain. If fusion does not progress from the anterior end of the neural plate (closure 3), the resultant phenotype is a split face usually accompanied by forebrain anencephaly.

Unlike the cranial region where closure proceeds bidirectionally, spinal neurulation is entirely caudally directed as the embryo continues to grow. Primary neurulation completes with final closure of the posterior neuropore on embryonic day 10. Impaired progression of closure, and consequently the presence of a persistently open posterior neuropore, results in spina bifida, and the size of the ensuing lesion relates directly to the axial level at which closure stops.

Diagrammatic representation of the developmental origin of malformations broadly classified as neural tube defects in humans. (a,b) Disorders of primary neurulation include craniorachischisis. (a) in which the neural tube fails to initiate closure, leaving most of the brain and the entire spine open. If closure initiates successfully, then the cranial and/or spinal neural folds may fail to close (b) generating exencephaly/anencephaly and open spina bifida (myelomeningocele), respectively. (c) Disorders of secondary neurulation comprise failure of the neural tube to separate completely from adjacent tissues, resulting in tethering and diminished mobility. The spinal cord is covered by skin and often associated with fatty tissue accumulation (lipoma) through as-yet-unknown mechanisms. (d) Postneurulation defects can arise when the bony structure of the skeleton fails to develop fully.

Primary Neurulation in Humans

Examination of human embryos suggests that initiation of closure is discontinuous, as in the mouse. Bending of the neural plate begins at approximately 18 days after fertilization, with an event equivalent to closure 1 at approximately 21 days and completion of closure at the posterior neuropore by 26--28 days postfertilization (Figure 1a,b). It appears that closure of the forebrain and midbrain in human embryos may be achieved by progression between the site of closure 1 and the rostral end of the neural plate without an intervening initiation site analogous to closure 2.

Secondary Neurulation

In mice and humans, the neural tube caudal to the midsacral region is continuous with the caudal end of the primary neural tube but forms by a distinct process, termed secondary neurulation . This process involves condensation of a population of tail bud--derived cells to form an epithelial rod that undergoes canalization to form the lumen of the tube in the lower sacral and coccygeal regions. Malformations resulting from disturbance of secondary neurulation are closed (skin covered) and often involve tethering of the spinal cord, with associated ectopic lipomatous material

Causes: NTDs are among the most common birth defects worldwide with a prevalence that varies from 0.5 to more than 10 per 1,000 pregnancies. This variance likely reflects differing contributions from risk factors such as nutritional status, prevalence of obesity and diabetes, usage of folic acid supplementation and/or fortification, the presence of environmental toxicants, and differing genetic predisposition among ethnic groups. In most populations, there is also a striking gender bias: Anencephaly is more prevalent among females than males. Many NTD mouse strains also show a female preponderance among cranial NTDs, apparently reflecting a fundamental higher sensitivity of cranial neural tube closure to disturbance in female embryos. Overall, although studies have identified numerous risk factors, these may account for less than half of NTDs, suggesting that additional genetic and nongenetic factors remain to be identified.