The curly tail mouse model of human neural tube defects demonstrates normal spinal cord differentiation at the level of the meningomyelocele: implications for fetal surgery

A role for all-trans-retinoic acid in spinal neurulation is suggested by: (1) the reciprocal domains of expression of the retinoic acid receptors RAR-beta and RAR-gamma in the region of the closed neural tube and open posterior neuropore, respectively, and (2) the preventive effect of maternally administered retinoic acid (5 mg/kg) on spinal neural tube defects in curly tail (ct/ct) mice. Using in situ hybridisation and computerised image analysis we show here that in ct/ct embryos, RAR-beta transcripts are deficient in the hindgut endoderm, a tissue whose proliferation rate is abnormal in the ct mutant, and RAR-gamma transcripts are deficient in the tail bud and posterior neuropore region. The degree of deficiency of RAR-gamma transcripts is correlated with the severity of delay of posterior neuropore closure. As early as 2 hours following RA treatment at 10 days 8 hours post coitum, i.e. well before any morphogenetic effects are detectable, RAR-beta expression is specifically upregulated in the hindgut endoderm, and the abnormal expression pattern of RAR-gamma is also altered. These results suggest that the spinal neural tube defects which characterise the curly tail phenotype may be due to interaction between the ct gene product and one or more aspects of the retinoic acid signalling pathway.

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Neural tube development in mutant (curly tail) and normal mouse embryos: the timing of posterior neuropore closure in vivo and in vitro

Development ◽

10.1242/dev.69.1.151 ◽

1982 ◽

Vol 69 (1) ◽

pp. 151-167

Author(s):

A. J. Copp ◽

M. J. Seller ◽

P. E. Polani

Keyword(s):

Neural Tube ◽

Neural Tube Defects ◽

Mouse Embryos ◽

Injection Technique ◽

Posterior Neuropore ◽

Curly Tail ◽

Mechanisms Of Development ◽

Delayed Closure

A dye-injection technique has been used to determine the developmental stage at which posterior neuropore (PNP) closure occurs in normal and mutant curly tail mouse embryos. In vivo, the majority of non-mutant embryos undergo PNP closure between 30 and 34 somites whereas approximately 50% of all mutant embryos show delayed closure, and around 20% maintain an open PNP even at advanced stages of development. A similar result has been found for embryos developing in vitro from the headfold stage. Later in development, 50–60% of mutant embryos in vivo develop tail flexion defects, and 15–20% lumbosacral myeloschisis. This supports the view that delayed PNP closure is the main developmental lesion leading to the appearance of caudal neural tube defects in curly tail mice. The neural tube is closed in the region of tail flexion defects, but it is locally overexpanded and abnormal in position. The significance of these observations is discussed in relation to possible mechanisms of development of lumbosacral and caudal neural tube defects. This paper constitutes the first demonstration of the development of a genetically induced malformation in vitro.

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Fetal Repair of Open Neural Tube Defects: Ethical, Legal, and Social Issues

Cambridge Quarterly of Healthcare Ethics ◽

10.1017/s0963180119000409 ◽

2019 ◽

Vol 28 (3) ◽

pp. 476-487 ◽

Cited By ~ 3

Author(s):

JULIA A.E. RADIC ◽

JUDY ILLES ◽

PATRICK J. MCDONALD

Keyword(s):

Neural Tube ◽

Neural Tube Defects ◽

Ethical Issues ◽

Social Issues ◽

Controlled Trial ◽

Fetal Surgery ◽

Close Monitoring ◽

Neurologic Outcomes ◽

Increased Risk ◽

Fetal Repair

Abstract:Open neural tube defects or myelomeningoceles are a common congenital condition caused by failure of closure of the neural tube early in gestation, leading to a number of neurologic sequelae including paralysis, hindbrain herniation, hydrocephalus and neurogenic bowel and bladder dysfunction. Traditionally, the condition was treated by closure of the defect postnatally but a recently completed randomized controlled trial of prenatal versus postnatal closure demonstrated improved neurologic outcomes in the prenatal closure group. Fetal surgery, or more precisely maternal-fetal surgery, raises a number of ethical issues that we address including who the patient is, informed consent, surgical innovation and equipoise as well maternal assumption of risk. As the procedure becomes more widely adopted into practice, we suggest close monitoring of new fetal surgery centers, in order to ensure that the positive results of the trial are maintained without increased risk to both the mother and fetus.

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