The formation of the secondary neural tube was traced in serial sections of human
embryos of developmental stages 13 to 17 (32-41 days after fertilisation). It was
found that the secondary neural tube formation begins with cavitation of the
neural cord. The minute cavities are seen in embryos at stages 13 and 15. At
stages 16 and 17 the numerous cavities coalesce to form a single central canal

Bruska, M.

Pytel, A.

Woźniak, W.

English

Via Medica Journals

Folia Morphol. Vol. 66, No. 2, pp. 104–108Copyright © 2007 Via MedicaISSN 0015–5659www.fm.viamedica.plO R I G I N A L   A R T I C L E104Address for correspondence: A. Pytel, MD, Department of Anatomy, University of Medical Sciences, Święcickiego 6, 60–195 Poznań,Poland, tel: +48 61 854 65 55, e-mail: anpy@mp.plEvidence that the caudal portion of the neuraltube develops by cavitation of a neural cordin the caudal eminence of human embryosA. Pytel, M. Bruska, W. WoźniakDepartment of Anatomy, University of Medical Sciences, Poznań, Poland[Received 11 March 2007; Accepted 19 April 2007]The formation of the secondary neural tube was traced in serial sections of humanembryos of developmental stages 13 to 17 (32–41 days after fertilisation). It wasfound that the secondary neural tube formation begins with cavitation of theneural cord. The minute cavities are seen in embryos at stages 13 and 15. Atstages 16 and 17 the numerous cavities coalesce to form a single central canal.Key words: human neuroembryology, secondary neurulation, neuralcord, cavitation, secondary neural tubeINTRODUCTIONThe central nervous system develops from a hol-low structure called the neural tube, which is pro-duced by neurulation. There are two neurulation pro-cesses, viz. primary and secondary neurulation [13,17–20].In the primary neurulation mechanism the neu-ral tube arises from the neural plate by folding andmidline fusion to form the primary neural tube (PNT)[1, 2]. In human embryos primary neurulation com-mences at stage 8 and extends to stage 12, whenthe posterior neuropore closes. This occurs when ap-proximately 24–26 somites are present. The site offinal closure corresponds approximately to futuresomite 31, the level of future sacral vertebra 2 (S2),which can be seen from stage 13 onwards [9]. Thislevel is considered to be the junction between theprimary and secondary neural tubes. The primaryneural tube gives rise to the brain and spinal corddown to the S2 level.Secondary neurulation involves the secondaryneural tube (SNT) formation from the pluripotentloosely associated mesenchymal cells of the caudaleminence (the end bud of tailed species) withoutdirect involvement of the surface ectoderm. It be-gins with the closure of the posterior neuropore(stage 12) and extends to about stages 17, 18 or 20[11, 12]. The caudal eminence mesenchyme com-prises a stem-cell population derived from the re-gressing primitive streak and Hensen’s node. It hasthe potential to create a variety of structures, includ-ing the caudal hind gut, coelom, blood vessels, no-tochord, somites and spinal cord. In the dorsal partof the caudal eminence mesenchymal cells undergocondensation and mesenchymal-neuroepithelialtransformation into the neural (medullary) cord,which subsequently cavitates (i.e. hollows out) togive rise to the secondary neural tube [5]. Typically,cavitation involves the coalescence of several small-er cavities into the central cavity or secondary neu-rocoel [19]. The primary neurocoel is continuous withthat of the secondary one. Secondary neurulationmakes up the lowest portion of the spinal cord, cau-dal to S2 level. The slow growth of the caudal neuraltube compared with the vertebrae results in the dis-placement of the junction area of the primary andsecondary neural tubes at higher (lumbosacral) levelin neonates [14].In the literature there is some controversy regard-ing the development of the secondary neural tubein human embryos. Müller and O’Rahilly [9, 10] ob-served a direct extension of the lumen of the primary105A. Pytel et al., Secondary neurulation in humansneural tube into that of the neural cord. No cavita-tion of the neural cord and no overlapping zone ofthe primary and secondary neural tubes were ob-served. These findings suggest that the secondaryneurulation in humans resembles that in mice[7, 12, 20]. On the other hand, some investigatorshave claimed that multiple cavities and overlappingzones were present in human secondary neural tubeformation as occurs in chick embryos [7, 8, 16, 18].The present study was undertaken to analyse theformation of the secondary neural tube in humanembryos of stages 13–17.MATERIAL AND METHODSTwelve human embryos from the Anatomy De-partment Collection of Poznań University of MedicalSciences ranging from 5, 0 to 14, 0 mm in crown-rump length, corresponding to the developmentalstages between 13 and 17 (32 to 41 days), were ex-amined microscopically (Table 1). All the embryoswere embedded in paraffin or paraplast and seriallysectioned in various planes at 5 or 10 µm thickness.The sections were stained according to the Mallorymethod, with haematoxylin and eosin, cresyl violetor toluidine blue according to Nissl’s method. Someof them were impregnated with Bodian’s protargol.The sections were photographed using a Canon S40digital camera and a total magnification was esti-mated with the aid of properly calibrated Carl ZeissAxioVision LE Release 4.5 analytical software.RESULTSIn embryos at stage 13 (32 days after fertilisa-tion) the ectodermal ridge and the cloacal membraneare positioned cranially to the caudal eminence andboth form a part of the ectodermal ring. This ridgehas an important function in epitheliomesenchymalinteraction. The neural cord reaches the tip of theembryo (Fig. 1).In the caudal eminence the somites, the neuralcord, notochord and gut may be distinguished (Fig. 2).In the neural cord, which consists of darkly stainedcells, minute cavities may be seen.During stages 14 (33 days after fertilisation) and15 (36 days after fertilisation) the mesenchyme with-in the caudal eminence is reduced and cavities inthe neural cord appear (Figs. 3, 4). These are largertoward the junctional area with the primary neuraltube and form a single cavity in the upper part ofthe neural tube (Fig. 5). The somites move to themidline.The development of the secondary neural tubeby cavitation is well seen at stage 16 (39 days afterfertilisation) and stage 17 (41 days after fertilisation).The neural tube is canalised by many cavities (Figs. 6, 7),which in the upper part form a single cavity (Fig. 8).Canalisation of the secondary neural tube proceedsin a cranial-to-caudal direction. A single lumen inthe upper part of the secondary neural tube becomescontinuous with the lumen of the primary neuraltube.Table 1. Developmental stage, age and plane of section of embryos investigatedCatalogue No. C-R length Developmental Age Plane[mm] stage [postfertilizational days] of sectionAP-41II WWA-19A-17B-175A-16IVB-180A-1B-129PJK-26.05.07.07.07.09.09.010.013.014.013.013.5131414141415151617171717323333333336363941414141SagittalHorizontalSagittalFrontalHorizontalHorizontalHorizontalHorizontalSagittalHorizontalSagittalHorizontal106Folia Morphol., 2007, Vol. 66, No. 2Figure 1. Sagittal section of embryo at stage 13; CM — cloacalmembrane; ER — ectodermal ridge; NC — neural cord.Figure 2. Sagittal section of embryo at stage 13; NC — neuralcord; N — notochord; G — gut; S — somite.Figure 3. Cross-section of embryo at stage 14; NC — neuralcord; N — notochord; G — gut; S — somite.Figure 4. Cross-section of embryo at stage 15; NC — neuralcord; N — notochord; G — gut; S — somite.Figure 5. Oblique section of embryo at stage 14; NT — neuraltube; N — notochord; S — somite.Figure 6. Cross-section of embryo at stage 16; NT — neuraltube; N — notochord.107A. Pytel et al., Secondary neurulation in humansDISCUSSIONThe development of the secondary neural tubein human embryos is still controversial [4, 12, 16].Knowledge of normal embryonic development of thecaudal neural tube is of great importance in under-standing the pathogenesis of neural tube defects inthe lumbosacral region [1, 6].Disturbances of secondary neurulation may leadto myelodysplasia, which may be manifest as spinaldysraphism or spina bifida occulta. A common ab-normality is tethered cord syndrome, in which theconus medullaris and the filum terminale are abnor-mally fixed to the defective vertebral column. Thesustained traction damages the cord, leading to lossof sensations from the legs and feet and problemswith bladder control [3]. Myelodysplasia is a part ofcaudal dysgenesis, the different forms of which maybe discovered later in life [15].The issue of whether secondary neurulation inhumans more closely resembles that in the chick orthe mouse is unresolved. In the chick embryo, sec-ondary neurulation results in the formation ofa medullary cord from dorsal cells of the caudalcell mass. Within this medullary cord cavitation cre-ates multiple tubules, the outer cells surroundinga central lumen, within which are the inner cells.Multiple smaller lumina coalesce to form larger cav-ities and a single lumen is formed [2]. Secondaryneurulation in the mouse begins with the forma-tion of a medullary rosette, a cluster of caudal masscells radially arranged about a central lumen formedby cavitation. The cells of the medullary rosette arethought to be the homologue of the outer cell groupin the chick embryo [2]. Caudal growth of the sec-ondary neural tube occurs by additional cavitation.In the mouse the secondary neural tube is directlycontinuous with the primary neural tube. The sec-ondary neural tube in the chick develops indepen-dently and only later fuses with the primary neuraltube. According to Lemire [8] and Hughes and Free-man [7], cavitation of the neural cord occurs ina manner similar to that in chickens. Müller andO’Rahilly [9, 10] did not find multiple cavities intheir specimens and argued that secondary neuru-lation involves extension of the primary neural ca-nal into the neural cord.Saitsu et al. [16] divided the secondary neuraltube into three parts: 1) the most rostral region,which corresponds to the posterior part of the pri-mary neural tube, 2) the junctional region of theprimary and secondary neural tubes and 3) the cau-dal region, which emerges from the neural cord. Inthe first two parts they found a single cavity and inthe third part of the secondary neural tube they fre-quently observed isolated cavities.The controversy over the development of the sec-ondary neural tube and the multiple cavities notedin the present study is evidence that this part of theneuraxis needs further investigation on extensiveembryonic material in which exact ages are estab-lished for the specimens investigated.REFERENCES1. Detrait ER, George TM, Etchevers HC, Gilbert JR,Vekemans M, Speer MC (2005) Human neural tubedefects: developmental biology, epidemiology, andgenetics. Neurotoxicol Teratol, 27: 515–524.2. Dias MS, Partington M (2004) Embryology of myelom-eningocele and anencephaly. Neurosurg Focus, 16: 1.Figure 7. Cross-section of embryo at stage 17; NT — neuraltube; N — notochord.Figure 8. Cross-section of embryo at stage 17; NT — neuraltube; N — notochord.108Folia Morphol., 2007, Vol. 66, No. 23. Evans OB, Hutchins JB (2006) Development of the ner-vous system. In: Haines DE ed. Fundamental Neurosciencefor Basic and Clinical Applications. Chapter 5. 3rd ed.Churchill Livingstone Elsevier, Philadelphia, pp. 69–88.4. Griffith CM, Wiley MJ, Sanders EJ (1992) The verte-brate tail bud: three germ layers from one tissue. AnatEmbryol, 185: 101–113.5. Griffith M (1997) Midkine and secondary neurulation.Teratology, 55: 213–223.6. Haque M, Ohata K, Takami T, Soares SB, Aree SN,Hakuba A, Hara M (2001) Development of lumbosac-ral spina bifida: three-dimensional computer graphicstudy of human embryos at Carnegie stage twelve.Pediatr Neurosurg, 35: 247–252.7. Hughes AF, Freeman RB (1974) Comparative remarkson the development of the tail cord among higher ver-tebrates. J Embryol Exp Morphol, 32: 355–363.8. Lemire RJ (1969) Variations in development of the cau-dal neural tube in human embryos (Horizons XIV-XXI).Teratology, 2: 361–370.9. Müller F, O’Rahilly R (1987) The development of thehuman brain, the closure of the caudal neuropore, andthe beginning of secondary neurulation at stage 12.Anat Embryol (Berl), 176: 413–430.10. Müller F, O’Rahilly R (1988) The development of thehuman brain from a closed neural tube at stage 13.Anat Embryol, 177: 203–224.11. Müller F, O’Rahilly R (2004) The primitive streak, thecaudal eminence and related structures in staged hu-man embryos. Cells Tissues Organs, 177: 2–20.12. Nievelstein RAJ, Hartwig NG, Vermeij-Keers C, Valk J(1993) Embryonic development of the mammaliancaudal neural tube. Teratology, 48: 21–31.13. O’Rahilly R, Müller F (1994) Neurulation in the normalhuman embryo. Ciba Found Symp, 181: 70–82 (dis-cussion 82–89).14. O’Rahilly R, Müller F (2003) Somites, spinal ganglia,and centra. Enumeration and interrelationships instaged human embryos, and implications for neuraltube defects. Cells Tiss Organs, 173: 75–92.15. Padmanabhan R, Naruse I, Shiota K (1999) Caudal dys-genesis in staged human embryos: Carnegie stages 16––23. Am J Med Genet, 87: 115–127.16. Saitsu H, Yamada S, Uwabe C, Ishibashi M, Shiota K(2004) Development of the posterior neural tube inhuman embryos. Anat Embryol, 209: 107–117.17. Saraga-Babic M, Lehtonen E, Svajger A, Wartiovaara J(1994) Morphological and immunohistochemical char-acteristics of axial structures in the transitory humantail. Ann Anat, 176: 277–286.18. Saraga-Babic M, Sapunar D, Wartiovaara J (1995) Vari-ations in the formation of the human caudal spinalcord. J Hirnforsch, 36: 341–347.19. Schoenwolf GC, Delongo J (1980) Ultrastructure ofsecondary neurulation in the chick embryo. Am J Anat,158: 43–63.20. Schoenwolf GC (1984) Histological and ultrastructur-al studies of secondary neurulation in mouse embry-os. Am J Anat, 169: 361–376.

Evidence that the caudal portion of the neural tube develops by cavitation of a neural cord in the caudal eminence of human embryos

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Evidence that the caudal portion of the neural tube develops by cavitation of a neural cord in the caudal eminence of human embryos

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