2009 Lecture 6

From Embryology

Ectoderm Development

Stage10 neural sm.jpg

== Introduction ==

This lecture will cover the early development of the ectoderm layer of the trilaminar embryo. Note that we will be returning later to discuss neural (central nervous system; brain and spinal cord) and neural crest (peripheral nervous system; sensory and sympathetic ganglia). Epidermis (integumentary, skin contribution) development will be briefly mentioned due to its ectoderm origin, but will also be covered later in the current course.

Lecture Objectives

  • Understanding of events during the third and fourth week of development
  • Understanding the process of notochord formation
  • Understanding the process of early neural development
  • Brief understanding of neural crest formation
  • Brief understanding of epidermis formation
  • Understanding of the adult components derived from ectoderm
  • Brief understanding of early neural abnormalities

Textbook References

  • Human Embryology (3rd ed.) Chapter 5 p107-125
  • The Developing Human: Clinically Oriented Embryology (6th ed.)

Other textbooks

  • Moore and Persaud Chapter 18 p451-489
  • Essentials of Human Embryology Larson Chapter 5 p69-79
  • Before We Are Born (5th ed.) Moore and Persaud Chapter 19 p423-458

UNSW Embryology Links

Lecture Summary

The following text is extracted and modified from 2008 lecture slides and should be used as a "trigger" to remind you of key concepts.

  • Early Neural Development (neuralation)
  • Mesoderm - axial process (mesoderm), notochordal plate, notochord
  • Ectoderm - neural plate, neural groove, neural tube, brain and spinal cord axes, neural tube layers, development of neurons and glia
  • Neural crest - orogins
  • Epidermis - ectoderm origins

Development Overview


  • forms initially as the Axial Process, a hollow tube which extends from the primitive pit , cranially to the oral membrane
  • the axial process then allow transient communication between the amnion and the yolk sac through the neuroenteric canal.
  • the axial process then merges with the Endodermal layer to form the Notochordal Plate.
  • the notochordal plate then rises back into the Mesodermal layer as a solid column of cells which is the Notochord.


  • 2 parts
  • midline neural plate
    • columnar
  • lateral surface ectoderm
    • cuboidal
    • sensory placodes
    • epidermis of skin, hair, glands, ant. pituitary, teeth enamel

Neural Plate

Neuralplate cartoon.png
  • extends from buccopharyngeal membrane to primitive node
  • forms above notochord and paraxial mesoderm
  • neuroectodermal cells
    • broad brain plate
    • narrower spinal cord
  • 3 components form: floor plate, neural plate, neural crest

Neural Determination- neuronal populations are specified before plate folds

  • signals from notochord and mesoderm - secrete noggin, chordin,follistatin
    • all factors bind BMP-4 an inhibitor of neuralation
    • bone morphogenic protein acts through membrane receptor
  • lateral inhibition generates at spinal cord level 3 strips of cells
  • expression of delta inhibits nearby cells, which express notch receptor, from becoming neurons
  • Delta-Notch inetraction- generates Neural strips

Neural Groove

  • forms in the midline of the neural plate (day 18-19)
  • either side of which are the neural folds which continues to deepen until about week 4
  • neural folds begins to fuse, beginning at 4th somite level

Neural Tube

  • the neural tube forms the brain and spinal cord
  • fusion of neural groove extends rostrally and caudally
  • begins at the level of 4th somite
  • closes neural groove "zips up" in some species.
    • humans appear to close at multiple points along the tube.
  • leaves 2 openings at either end - Neuropores
    • cranial neuropore closes before caudal

Secondary Neuralation

  • caudal end of neural tube formed by secondary neuralation
  • develops from primitive streak region
  • solid cord canalized by extension of neural canal
  • mesodermal caudal eminence

Neural Tube Defects (NTD)

    • failure of neural tube closure
    • severity dependent upon level, spina bifida anancephaly (More? Neural Abnormalities)
    • found that supplementation of maternal diet with folate reduces incidence of NTDs
    • A randomised controlled trial conducted by the Medical Research Council of the United Kingdom demonstrated a 72% reduction in risk of recurrence by periconceptional (ie before and after conception) folic acid supplementation (4mg daily).
    • Women who have one infant with a neural tube defect have a significantly increased risk of recurrence (40-50 per thousand compared with 2 per thousand for all births)

Neural Crest

Neural Crest Notes

  • a population of cells at the edge of the neural plate that lie dorsally when the neural tube fuses
    • dorsal to the neural tube, as a pair of streaks
    • pluripotential, forms many different types of cells
    • cells migrate throughout the embryo
    • studied by quail-chick chimeras
    • transplanted quail cells have obvious nucleoli compared with chicken

Neural Crest Derivitives

  • dorsal root ganglia
  • autonomic ganglia
  • adrenal medulla
  • drg sheath cells, glia
  • pia-arachnoid sheath
  • skin melanocytes
  • connective tissue of cardiac outflow
  • thyroid parafollicular cells
  • craniofacial skeleton
  • teeth odontoblasts

Early Brain Structure

Primary Vesicles

  • rostral neural tube forms 3 primary brain vesicles (week 4)
  • 3 primary vesicles: prosencephalon (forebrain), mesencephalon (midbrain), rhombencephalon (hindbrain)

Secondary Vesicles

From the 3 primary vesicles developing to form 5 secondary vesicles

  • prosencephalon- telencephalon (endbrain, forms cerebral hemispheres), diencephalon (betweenbrain, forms optic outgrowth)
  • mesencephalon
  • rhombencephalon- metencephalon (behindbrain), myelencephalon (medullabrain)


MH - this will be covered in detail in later neural development

  • cavity within tube will form the contiguious space of the ventricules of the brain and central canal of spinal cord
  • this space is filled initially with amniotic fluid, later with CerebroSpinal Fluid (CSF)
  • CSF is secreted by a modified vascular structure, the chorioid plexus, lying within the ventricles

Brain Flexures

Rapid growth folds the neural tube forming 3 brain flexures

  • cervical flexure - between brain stem and spinal cord
  • midbrain flexure - pushes mesencephalon upwards
  • pontine flexure - generates 4th ventricle

Neural Layers

  • neural stem cells lie in the layer closest to the ventricular space, the ventricular layer
    • this layer generates both neuroblasts and glioblasts
  • neuroblasts arise first and migrate along radial gial
  • their migration stops at cortical plate

Spinal Cord Axes

Identified by experimental manipulation of interactions.

  • Initial experiments looked at how isolated tissues may influence the development of the spinal cord.
  • Repositionining of specific tissues both in vivo and in vitro
  • specific markers of or alteration of differentiation. Notocord Induction

Ventral Axis

  • Sonic Hedgehog - notochord secretes sonic hedgehog
  • Gene expression studies (ISH) showed shh gene expression occured in a subset of inducing tissues
  • has a patterning role elsewhere (limb, sclerotome, lung)
  • 2 signaling activities acting (locally and at a distance) Ventral- Sonic Hedgehog
  • Binds to cell surface receptor patched
  • without shh, patched (Ptc) binds smoothened (Smo)
  • with shh shh-Ptc releases Smo activating G protein pathway Gene Diseases
  • shh Human mutation- holoprosencephaly 3
    • characteristic faces of the severe form of HPE which included a single fused eye (cyclopia) and a nose-like structure (proboscis) above the eye
    • Downstream targets of Sonic hedgehog signalling:
      • transcription factors like Gli3 (responsible for Greigs polycephalosyndactyly in humans)
      • d Hoxd13 (responsible for polysyndactyly)

Dorsal Axis

  • Dorsalin - ectoderm secretes a growth factor shown to controls patterning in embryonic mesoderm (frog)
    • Transforming Growth factor beta, (TGF b), related factors BMP-2, BMP-4, BMP-7, radar (flies related protein determines dorsoventral)
    • homology search of vertebrate library identified protein of same family.
    • dorsalin-1 (dsl-1) (Basler, Cell 73, p687, 1993) Dorsalin-1
    • From overlying ectoderm
    • Naming comes from the obvious reason that it promotes the differentiation of neural crest cells.
    • Also signal for dorsal signal of neural tube.
    • Inhibits the differentiation of motoneurons.
    • Implication is that dsl-1 and shh act antagonistically, or competitively to establish d-v axis of neural tube.

Rostro-Caudal Axis

  • Brain rostro-caudal axis is generated by differential expression of Hox genes (transcriptional activators)
    • corresponding to genetic order on chromosome. (Wilkinson, Nature, 341, p405, 1989) Hox Genes
    • Stands for Homeobox domain Genes
    • A family of transcription factors
    • Discovered in flies and conserved between all species. [../OtherEmb/fly.htm#antennapedia antennapedia]
    • Expressed in sequence along the embryo rostro-caudal axis.
    • Regulate many other aspects of development.
    • 180aa region binds DNA and regulate gene expression
    • large family of genes organized and expressed in sequence on the chromosome
    • Nkx-2.2 first detected at 1 somite stage
    • Lim hox gene expressed at spinal cord level

Ectodermal Placodes

  • Specialized ectodermal "patches" in the head region
  • Contribute sensory structures - otic placode (otocyst), nasal placode, lens placode
  • Contribute teeth

Neural tube and Genes: neural specification- Notch/Delta, patched receptor. Border- fibroblast growth factor (fgf), BMP (BMP4, msx1) Rostral border- Dlx5 Neural tube patterning

    • segmented along its length- Hox/Lim gene expression
    • ventral identity- sonic hedgehog, BMP7/chordin interaction
    • dorsal identity- dorsalin

Human Neuralation - Early Stages

The stages below refer to specific Carneigie stages of development.

  • stage 8 (about 18 postovulatory days) neural groove and folds are first seen
  • stage 9 the three main divisions of the brain, which are not cerebral vesicles, can be distinguished while the neural groove is still completely open.
  • stage 10 (two days later) neural folds begin to fuse near the junction between brain and spinal cord, when neural crest cells are arising mainly from the neural ectoderm
  • stage 11 (about 24 days) the rostral (or cephalic) neuropore closes within a few hours; closure is bidirectional, it takes place from the dorsal and terminal lips and may occur in several areas simultaneously. The two lips, however, behave differently.
  • stage 12 (about 26 days) The caudal neuropore takes a day to close
  • the level of final closure is approximately at future somitic pair 31
  • corresponds to the level of sacral vertebra 2
  • stage 13 (4 weeks) the neural tube is normally completely closed

Secondary neurulation begins at stage 12

  • is the differentiation of the caudal part of the neural tube from the caudal eminence (or end-bud) without the intermediate phase of a neural plate.

(Stage text modified from: Neurulation in the normal human embryo. O'Rahilly R, Muller F Ciba Found Symp 1994;181:70-82)

Critical Periods of Human Development to Teratogens

UNSW Embryology Links

Internet Links

Embryo Images Early Cell Populations and Establishment of Body Form | Nervous System Development

Society for Neuroscience http://web.sfn.org/content/Publications/BrainFacts/index.html Brain Facts

Anatomy of the Human Body The Neural Groove and Tube

Glossary Links

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