Spinal neural tube formation and tail development in human embryos.

Primary and secondary neurulation - processes that form the spinal cord - are incompletely understood in humans, largely due to the challenge of accessing neurulation-stage embryos (3-7 weeks post-conception). Here, we describe findings from 108 human embryos, spanning Carnegie stages (CS) 10-18. Primary neurulation is completed at the posterior neuropore with neural plate bending that is similar, but not identical, to the mouse. Secondary neurulation proceeds from CS13 with formation of a single lumen as in mouse, not coalescence of multiple lumens as in chick. There is no evidence of a 'transition zone' from primary to secondary neurulation. Secondary neural tube 'splitting' occurs in 60% of proximal human tail regions. A somite is formed every 7 hr in human, compared with 2 hr in mice and a 5 hr 'segmentation clock' in human organoids. Termination of axial elongation occurs after down-regulation of WNT3A and FGF8 in the CS15 embryonic tailbud, with a 'burst' of apoptosis that may remove neuro-mesodermal progenitors. Hence, the main differences between human and mouse/rat spinal neurulation relate to timing. Investigators are now attempting to recapitulate neurulation events in stem cell-derived organoids, and our results provide 'normative data' for interpretation of such research findings.