Spinal neural tube formation and regression in human embryos

Abstract

Formation of the nervous system in the spinal region of higher vertebrates involves primary and secondary neurulation, in which the neural tube forms by closure and canalisation respectively. These processes are incompletely understood in humans, in part due to the challenge of accessing neurulation-stage embryos (3-7 weeks post-conception). Here we present findings on completion of primary neurulation and formation of the secondary body (including secondary neurulation) in 108 human embryos that span Carnegie Stages (CS) 10 to 18. Several outstanding questions on low spinal development in humans are addressed: we show that primary neurulation is completed at the human posterior neuropore with a pattern of neural plate bending similar to that in the mouse. There is no evidence of a transition zone to secondary neurulation, which proceeds from CS13 with formation of a single lumen as in mouse, not coalescence of multiple lumens as has been claimed based on chick neurulation. Secondary neural tube splitting is seen in the more proximal tail regions of 60% of human embryos. A somite is formed every 7 h in human, compared with 2 h in mice and a 5 h segmentation clock in human organoids. Termination of axial elongation occurs after downregulation of WNT3A and FGF8 in the CS15 embryonic tailbud, with a burst of apoptosis that may remove the neuro-mesodermal progenitors. We conclude that low spinal neurulation and secondary body formation follow a similar pattern in humans as in mammalian model systems such as mouse and rat. Investigators are now attempting to recapitulate events of neurulation in organoids derived from human stem cells, and our findings provide normative data for interpretation of such in vitro results.