Notochord

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Introduction

Human notochordal process and notochordal canal (Carnegie stage 8)

The notochord (axial mesoderm, notochordal process) is the defining structure forming in all chordate embryos (taxonomic rank: phylum Chordata). It is an early forming midline structure in the trilaminar embryo mesoderm layer initially ventral to the ectoderm, then neural plate and finally neural tube. This is a transient embryonic anatomy structure, not existing in the adult, required for patterning the surrounding tissues. The patterning signal secreted by notochord cells is sonic hedgehog (SHH). This secreted protein binds to receptors on target cells activating a signaling pathway involved in that tissues differentiation and development. This response appears to be concentration dependent, that is the closer to the notochord the higher the SHH concentration.


Thought to have at least 2 early roles in development and later roles in patterning surrounding tissues. 1. Mechanical, influencing the folding of the early embryo; 2. Morphogenic, secreting sonic hedgehog a protein which regulates the development of surrounding tissues (neural plate, somites, endoderm and other organs).

Recent work in chicken[1] suggests that the later patterning of vertebral segmentation is driven by the somite sclerotome, a result which differs from the findings in the zebrafish model.[2]


In humans, the notochord forms in week 3, is eventually lost from vertebral regions and contributes the entire nucleus pulposus[3] of the intervertebral disc during the formation of the vertebral column.


Notochord Links: notochord | Lecture - Week 3 | sonic hedgehog | Week 3 | stage 7 | stage 8 | epithelial mesenchymal transition | Development Animation - Notochord | neural | axial skeleton | musculoskeletal | gastrulation | Category:Notochord
Historic Embryology - Notochord 
1902 Notochord | 1908 Mammalian notochord

Some Recent Findings

Human notochord development theories
Human notochord development theories[4]
  • The development of the human notochord[4] "The notochord is a major regulator of embryonic patterning in vertebrates and abnormal notochordal development is associated with a variety of birth defects in man. Our analysis and three-dimensional (3D) reconstructions of 27 sectioned human embryos ranging from Carnegie Stage 8 to 15 (17-41 days of development), resulted in a comprehensive and verifiable new model of notochordal development. Subsequent to gastrulation, a transient group of cells briefly persists as the notochordal process which is incorporated into the endodermal roof of the gut while its dorsal side attaches to the developing neural tube. Then, the notochordal process embeds entirely into the endoderm, forming the epithelial notochordal plate, which remains intimately associated with the neural tube. Subsequently, the notochordal cells detach from the endoderm to form the definitive notochord, allowing the paired dorsal aortae to fuse between the notochord and the gut. We show that the formation of the notochordal process and plate proceeds in cranio-caudal direction. Moreover, in contrast to descriptions in the modern textbooks, we report that the formation of the definitive notochord in humans starts in the middle of the embryo, and proceeds in both cranial and caudal directions."
  • The role of the notochord in amniote vertebral column segmentation[1] "The vertebral column is segmented, comprising an alternating series of vertebrae and intervertebral discs along the head-tail axis. The vertebrae and outer portion (annulus fibrosus) of the disc are derived from the sclerotome part of the somites, whereas the inner nucleus pulposus of the disc is derived from the notochord. Here we investigate the role of the notochord in vertebral patterning through a series of microsurgical experiments in chick embryos. Ablation of the notochord causes loss of segmentation of vertebral bodies and discs. However, the notochord cannot segment in the absence of the surrounding sclerotome. To test whether the notochord dictates sclerotome segmentation, we grafted an ectopic notochord. We find that the intrinsic segmentation of the sclerotome is dominant over any segmental information the notochord may possess, and no evidence that the chick notochord is intrinsically segmented. We propose that the segmental pattern of vertebral bodies and discs in chick is dictated by the sclerotome, which first signals to the notochord to ensure that the nucleus pulposus develops in register with the somite-derived annulus fibrosus. Later, the notochord is required for maintenance of sclerotome segmentation as the mature vertebral bodies and intervertebral discs form. These results highlight differences in vertebral development between amniotes and teleosts including zebrafish, where the notochord dictates the segmental pattern. The relative importance of the sclerotome and notochord in vertebral patterning has changed significantly during evolution." chicken
  • Segmentation of the zebrafish axial skeleton relies on notochord sheath cells and not on the segmentation clock[2] "Segmentation of the axial skeleton in amniotes depends on the segmentation clock which patterns the paraxial mesoderm and the sclerotome. While the segmentation clock clearly operates in teleosts, the role of the sclerotome in establishing the axial skeleton is unclear. We severely disrupt zebrafish paraxial segmentation, yet observe a largely normal segmentation process of the chordacentra. We demonstrate that axial entpd5+ notochord sheath cells are responsible for chordacentrum mineralization, and serve as a marker for axial segmentation. While autonomous within the notochord sheath, entpd5 expression and centrum formation show some plasticity and can respond to myotome pattern. These observations reveal for the first time the dynamics of notochord segmentation in a teleost, and are consistent with an autonomous patterning mechanism that is influenced, but not determined by adjacent paraxial mesoderm. This behavior is not consistent with a clock-type mechanism in the notochord." zebrafish
More recent papers  
Mark Hill.jpg
PubMed logo.gif

This table shows an automated computer PubMed search using the listed sub-heading term.

  • Therefore the list of references do not reflect any editorial selection of material based on content or relevance.
  • References appear in this list based upon the date of the actual page viewing.

References listed on the rest of the content page and the associated discussion page (listed under the publication year sub-headings) do include some editorial selection based upon both relevance and availability.

Links: References | Discussion Page | Pubmed Most Recent | Journal Searches


Search term: Notochord

Xing Chen, Mingliang Fang, Melissa Chernick, Feng Wang, JingfengYang, Yongli Yu, Na Zheng, Hiroki Teraoka, Satomi Nanba, Takeo Hiraga, David E Hinton, Wu Dong The case for thyroid disruption in early life stage exposures to thiram in zebrafish (Danio rerio). Gen. Comp. Endocrinol.: 2018; PubMed 30408483

Lindsay E Ratcliffe, Emmanuel K Asiedu, C J Pickett, Megan A Warburton, Stephanie A Izzi, Thomas H Meedel The Ciona Myogenic Regulatory Factor Functions as a Typical MRF but Possesses a Novel N-terminus that is Essential for Activity. Dev. Biol.: 2018; PubMed 30365920

Saime G Sagiroglu, Sezen Koçaslan, Selman Sarica, Nagihan Bilal, Israfil Orhan Clinical and Histopathological Findings of Chordomas: a Case Report. Folia Med (Plovdiv): 2018, 60(3);468-473 PubMed 30355831

Praveen Barrodia, Chinmoy Patra, Rajeeb K Swain EF-hand domain containing 2 (Efhc2) is crucial for distal segmentation of pronephros in zebrafish. Cell Biosci: 2018, 8;53 PubMed 30349665

Karel de Bree, Bernadette S de Bakker, Roelof-Jan Oostra The development of the human notochord. PLoS ONE: 2018, 13(10);e0205752 PubMed 30346967

Older papers  
These papers originally appeared in the Some Recent Findings table, but as that list grew in length have now been shuffled down to this collapsible table.

See also the Discussion Page for other references listed by year and References on this current page.

  • Mechanical control of notochord morphogenesis by extra-embryonic tissues in mouse embryos[5] "Here, we show that in mouse embryos, the expansion of the amniotic cavity (AC), which is formed between embryonic and extraembryonic tissues, provides the mechanical forces required for a type of morphogenetic movement of the notochord known as convergent extension (CE) in which the cells converge to the midline and the tissue elongates along the antero-posterior (AP) axis. The notochord is stretched along the AP axis, and the expansion of the AC is required for CE. Both mathematical modeling and physical simulation showed that a rectangular morphology of the early notochord caused the application of anisotropic force along the AP axis to the notochord through the isotropic expansion of the AC. AC expansion acts upstream of planar cell polarity (PCP) signaling, which regulates CE movement. Our results highlight the importance of extraembryonic tissues as a source of the forces that control the morphogenesis of embryos."
  • Transcriptional profiling of the nucleus pulposus: say yes to notochord[3] "This editorial addresses the debate concerning the origin of adult nucleus pulposus cells in the light of profiling studies by Minogue and colleagues. In their report of several marker genes that distinguish nucleus pulposus cells from other related cell types, the authors provide novel insights into the notochordal nature of the former. Together with recently published work, their work lends support to the view that all cells present within the nucleus pulposus are derived from the notochord. Hence, the choice of an animal model for disc research should be based on considerations other than the cell loss and replacement by non-notochordal cells."
  • Notochord-derived BMP antagonists inhibit endothelial cell generation and network formation[6] "Embryonic blood vessel formation is initially mediated through the sequential differentiation, migration, and assembly of endothelial cells (ECs). ...We have previously shown that the notochord is responsible for the generation and maintenance of the avascular midline and that BMP antagonists expressed by this embryonic tissue, including Noggin and Chordin, can mimic this inhibitory role. Here we report that the notochord suppresses the generation of ECs from the mesoderm both in vivo and in vitro."

Notochord Development

Stage8 sem1.jpg Human Embryo notochordal plate

A scanning electron micrograph (SEM) image of the human embryo (Carnegie stage 8, day 15).

The notochordal plate is the initial early transient cellular structure and region lying above the primitive streak, that will later be converted into the notochord.

Click Here to play on mobile device

This animation shows the early development of the notochord occurring during week 3 of human development.

This is a dorsal view of the embryonic disc, caudal (tail and connecting stalk end) to the bottom and rostral (head end) to the top. The indentations show the location of the cloacal (bottom) and buccopharyngeal (top) membranes. The raised region in the middle of the embryonic disc is the primitive node (Hensen's node).

The right hand side of the gastrulating embryonic disc is removed to the midline to show the the position of the initial axial process (purple). As the animation plays the axial process extends rostrally from the primitive node towards the buccopharyngeal membrane, where it stops.

A cross-section view above the primitive node is shown in the second animation below.


Grey - epiblast forming ectoderm | Yellow - endoderm | Orange - mesderm | Purple - axial process


Links: MP4 version | Notochord Movie

Click Here to play on mobile device


This animation shows the early development of the notochord in relation to the endoderm in the trilaminar embryo.

The view is a cross-section showing how the axial process initially is formed, then fused with the endoderm, to finally separate as a midline mesoderm structure.


Yellow - endoderm | Purple - axial process


Links: MP4 version | Notochord Movie

Patterning

Notochord secreting sonic hedgehog (shown in white)
Neuralplate cartoon.png Somite cartoon5.png
Neural tube patterning Somite patterning


Development

Week 3

Neuroenteric Canal Notochordal Plate
Human Embryo Neuroenteric Canal Human Embryo Notochordal Plate
Human Embryo SEM (Stage 8, day 18)

The primitive streak, the caudal eminence and related structures in staged human embryos.[7]

"The neurenteric canal is an important landmark because rostral to it the neural plate of stages 8, 9, and the main part of the notochord develop, whereas caudal to it the neural plate of stages (10, 11, 12) and the caudal portion of the notochord are formed. All somites at stages 9-11 and probably also at stage 12 arise rostral to the site of the neurenteric canal. (2) A 'chordoneural hinge."

Week 4

Stage11 sem100.jpg

Human embryo 25 days, 19 somite pairs Scanning EM. (Carnegie stage 11)


Week 8

Stage22 vertebra and spinal cord 1.jpg

Vertebra and Spinal cord (Carnegie Stage 22)

Nucleus Pulposus

The notochord is a developmental patterning structure. The only adult anatomy derived from the notochord is the nucleus pulpous of the intervertebral disc.[3]

The embryonic notochordal cells are replaced postnatally by fibrocartilage (about 11 years of age). Composed of a jelly-like material and a loose network of collagen fibres, its physical properties allow the vertebral disc to withstand forces of compression and torsion.

Ossification endochondral 1c.jpg

Nucleus pulpous of the intervertebral disc

Gray0065.jpg

Historic schematic for axial skeleton segmentation

Mouse Notochord

Mouse (E11) Notochord labeling HNF3beta[8]
Mouse embryo E11 HNF3beta notochord marker 02.jpg Mouse embryo E11 HNF3beta notochord marker 03.jpg Mouse embryo E11 HNF3beta notochord marker 04.jpg
  • nc; notochord, fp; floor plate.
  • lb; lung bud, hg; hindgut, st; stomach.
  • HNF3beta - FORKHEAD BOX A2 (FOXA2) Hepatocyte nuclear factor 3β (HNF3β)


Links: Image 1 - E11 Notochord | Image 2 - E11 Notochord | Image 3 - E11 Notochord | Image 4 - E11 Notochord | Notochord | Mouse Development | Category:Mouse E11.0 | Image- Mouse embryo E11 and tomography | Image - Mouse embryo E11 tomography | OMIM FORKHEAD BOX A2

Molecular Factors

Xenopus FoxA4 model
PMID25343614}}

The notochord secretes both sonic hedgehog (SHH) and Vascular Endothelial Growth Factor (VEGF) as a molecular patterning signals.


Links: OMIM - SONIC HEDGEHOG; SHH | OMIM - T BRACHYURY

Abnormalities

Abnormalities include remnants of notochord that fail to regress. Locations can be along the embryonic path of the notochord and include: ecchordosis physaliphora, odontoid process of the axis, and in the coccyx. Less common locations are in the nasopharynx (Tornwaldt's cysts).

Ecchordosis physaliphora

Benign ectopic nests found along the craniospinal axis forming from notochordal remnants.[9]

Ecchordosis physaliphora radiography.jpg

Brain radiography showing (A) Axial CTA (bone window); (B) Sagittal T1 MRI; (C) Sagittal T2 MRI showing EP and pontine telangiectasia; (D) CTA showing fenestrated basilar artery.[9]

Tornwaldt's cysts

A rare nasopharyngeal lesion occurring in humans thought to develop from remnants of the embryonic notochord adjacent with the embryonic foregut.[10][11]These cysts are covered by the nasopharynx mucous membrane. Named after Gustav Ludwig Tornwaldt (1843 - 1910) a German physician, the name is also spelled Thornwaldt.

Chordoma

Rare type of bone cancer arising from remnants of the embryonic notochord (for review see{{pmid:26363792|PMID26363792}}) Nearly all chordomas express the T-box transcription factor (TBX) brachyury.


Links: Tbx | OMIM Chordoma | chordoma foundation

Benign Notochordal Cell Tumour

Benign notochordal cell tumours (BNCTs) may have a relationship with the bones of the base of the skull. The difference between this condition and a chordoma is the absence of extracellular matrix and eosinophil cells and the presence of vacuoles in most tumour cells. Genetically, in contrast to chordoma, chromosome gain or normal copy number was more common while chromosome loss was infrequent in BNCTs. [12]


References

  1. 1.0 1.1 Ward L, Pang ASW, Evans SE & Stern CD. (2018). The role of the notochord in amniote vertebral column segmentation. Dev. Biol. , , . PMID: 29654746 DOI.
  2. 2.0 2.1 LLeras Forero L, Narayanan R, Huitema LFA, VanBergen M, Apschner A, Peterson-Maduro J, Logister I, Valentin G, Morelli LG, Oates A & Schulte-Merker S. (2018). Segmentation of the zebrafish axial skeleton relies on notochord sheath cells and not on the segmentation clock. Elife , 7, . PMID: 29624170 DOI.
  3. 3.0 3.1 3.2 Shapiro IM & Risbud MV. (2010). Transcriptional profiling of the nucleus pulposus: say yes to notochord. Arthritis Res. Ther. , 12, 117. PMID: 20497604 DOI.
  4. 4.0 4.1 de Bree K, de Bakker BS & Oostra RJ. (2018). The development of the human notochord. PLoS ONE , 13, e0205752. PMID: 30346967 DOI.
  5. Imuta Y, Koyama H, Shi D, Eiraku M, Fujimori T & Sasaki H. (2014). Mechanical control of notochord morphogenesis by extra-embryonic tissues in mouse embryos. Mech. Dev. , 132, 44-58. PMID: 24509350 DOI.
  6. Bressan M, Davis P, Timmer J, Herzlinger D & Mikawa T. (2009). Notochord-derived BMP antagonists inhibit endothelial cell generation and network formation. Dev. Biol. , 326, 101-11. PMID: 19041859 DOI.
  7. Müller F & O'Rahilly R. (2004). The primitive streak, the caudal eminence and related structures in staged human embryos. Cells Tissues Organs (Print) , 177, 2-20. PMID: 15237191 DOI.
  8. Hajduk P, Sato H, Puri P & Murphy P. (2011). Abnormal notochord branching is associated with foregut malformations in the adriamycin treated mouse model. PLoS ONE , 6, e27635. PMID: 22132119 DOI.
  9. 9.0 9.1 Lagman C, Varshneya K, Sarmiento JM, Turtz AR & Chitale RV. (2016). Proposed Diagnostic Criteria, Classification Schema, and Review of Literature of Notochord-Derived Ecchordosis Physaliphora. Cureus , 8, e547. PMID: 27158576 DOI.
  10. Miyahara H & Matsunaga T. (1994). Tornwaldt's disease. Acta Otolaryngol Suppl , 517, 36-9. PMID: 7856446
  11. Moody MW, Chi DH, Chi DM, Mason JC, Phillips CD, Gross CW & Schlosser RJ. (2007). Tornwaldt's cyst: incidence and a case report. Ear Nose Throat J , 86, 45-7, 52. PMID: 17315835
  12. Du J, Xu L, Cui Y, Liu Z, Su Y & Li G. (2018). Benign notochordal cell tumour: clinicopathology and molecular profiling of 13 cases. J. Clin. Pathol. , , . PMID: 30355586 DOI.

Reviews

Lawson LY & Harfe BD. (2017). Developmental mechanisms of intervertebral disc and vertebral column formation. Wiley Interdiscip Rev Dev Biol , 6, . PMID: 28719048 DOI.

Risbud MV & Shapiro IM. (2011). Notochordal cells in the adult intervertebral disc: new perspective on an old question. Crit. Rev. Eukaryot. Gene Expr. , 21, 29-41. PMID: 21967331

Risbud MV, Schaer TP & Shapiro IM. (2010). Toward an understanding of the role of notochordal cells in the adult intervertebral disc: from discord to accord. Dev. Dyn. , 239, 2141-8. PMID: 20568241 DOI.

Stemple DL. (2005). Structure and function of the notochord: an essential organ for chordate development. Development , 132, 2503-12. PMID: 15890825 DOI.

Articles

Imuta Y, Koyama H, Shi D, Eiraku M, Fujimori T & Sasaki H. (2014). Mechanical control of notochord morphogenesis by extra-embryonic tissues in mouse embryos. Mech. Dev. , 132, 44-58. PMID: 24509350 DOI.

Korecki CL, Taboas JM, Tuan RS & Iatridis JC. (2010). Notochordal cell conditioned medium stimulates mesenchymal stem cell differentiation toward a young nucleus pulposus phenotype. Stem Cell Res Ther , 1, 18. PMID: 20565707 DOI.

Christiansen HE, Lang MR, Pace JM & Parichy DM. (2009). Critical early roles for col27a1a and col27a1b in zebrafish notochord morphogenesis, vertebral mineralization and post-embryonic axial growth. PLoS ONE , 4, e8481. PMID: 20041163 DOI.

Edeling MA, Sanker S, Shima T, Umasankar PK, Höning S, Kim HY, Davidson LA, Watkins SC, Tsang M, Owen DJ & Traub LM. (2009). Structural requirements for PACSIN/Syndapin operation during zebrafish embryonic notochord development. PLoS ONE , 4, e8150. PMID: 19997509 DOI.

Lee JD & Anderson KV. (2008). Morphogenesis of the node and notochord: the cellular basis for the establishment and maintenance of left-right asymmetry in the mouse. Dev. Dyn. , 237, 3464-76. PMID: 18629866 DOI.

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Search NLM Online Textbooks: "Notochord" : Developmental Biology | The Cell- A molecular Approach | Molecular Biology of the Cell | Endocrinology


Search Pubmed: Notochord

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Cite this page: Hill, M.A. (2018, November 16) Embryology Notochord. Retrieved from https://embryology.med.unsw.edu.au/embryology/index.php/Notochord

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