Genetics and Developmental Biology of Closed Dysraphic Conditions

Abstract

Closed spinal dysraphic conditions are typically considered malformations of caudal development, and have prompted intense speculation on possible pathogenic mechanisms. Ultimately, an understanding of developmental processes, both normal and abnormal, requires an experimental evidence base. This chapter surveys the experimental literature for clues to the genetics and developmental biology of human spinal dysraphism, based largely on studies in mouse models.Current trends in human disease gene identification, and the development of mouse genetic disease models, are reviewed, as well as several key areas of developmental biology progress that relate to development of the caudal body axis. Open neural tube defects (e.g. myelomeningocele) are relatively well understood owing to the many mouse models of faulty neural tube closure. Closed lesions in which the spinal cord is tethered and associated with spinal lipoma are much less well represented in mouse models; only preliminary clues to their likely developmental origins can currently be discerned. Some closed sacro-caudal conditions have a more defined genetic and developmental biology basis: for example, dorsal and ventral vertebral anomalies, caudal regression syndrome and Currarino triad. A future concerted research effort is needed to bring together clinical observations with research in developmental biology in this important area of pediatric clinical management.

RosetteArray®Platform for Quantitative High-Throughput Screening of Human Neurodevelopmental Risk

“…Yet, in the 12-well cervical SC RosetteArray, there was complete abrogation of rosette emergence accompanied by a significant decrease in cell viability/proliferation and neural induction in the SCRIB KO line compared to the SCRIB P1043L(+/−) and SCRIB P1043L(−/−) lines ( Figure 7G,H, L-N ). This regional NTD risk phenomenon in the SCRIB KO line comports with the SCRIB Crc mouse 75 and human 76 presentation of craniorachischisis (CRN), which is a failure of neural tube closure across the neuraxis except for the rostral forebrain 77 . Also, despite SCRIB’s p.P1043L mutation in its third PDZ domain, immunostaining showed apical co-localization of SCRIB and F-Actin (phalloidin) in both FB and cervical SC rosettes formed using SCRIB P1043L(+/−) and SCRIB P1043L(−/−) lines ( Figure S16C ).…”

Spinal neural tube formation and regression in human embryos

“…Closed 'dysraphic' conditions arise at lower sacral and coccygeal levels of the body axis and result from disturbance of secondary neurulation, in which the neural tube forms by a process of canalisation, without formation of neural folds. Dysraphic conditions involve an abnormal anatomical relationship between secondary neural tube and surrounding tissues, often with ectopic adipose tissue, as in spinal lipoma and lipomyelomeningocele (Jones et al, 2019 ). Closed dysraphism may be asymptomatic, but significant disability can occur through tethering of the low spinal cord to non-neural tissues (Agarwalla et al, 2007 ).…”

Spinal neural tube formation and regression in human embryos

“…Dysraphic conditions involve an abnormal anatomical relationship between secondary neural tube and surrounding tissues, often with ectopic adipose tissue, as in spinal lipoma and lipomyelomeningocele (Jones et al, 2019). Closed dysraphism may be asymptomatic, but significant disability can occur through tethering of the low spinal cord to non-neural tissues (Agarwalla et al, 2007).…”