2009 Lecture 6
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.
- 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
- Human Embryology (3rd ed.) Chapter 5 p107-125
- The Developing Human: Clinically Oriented Embryology (6th ed.)
- 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
- Ectoderm Slides Neural Lecture 5 2008 | Neural Lecture 2008 - 1 slide/page | Neural 2008 Slides - 4 slides/page | Neural Lecture 2008 Slides - 6 slides/page
- Ectoderm Movies Notochord | Notochord | Neural Plate | Neurulation | Secondary Neurulation
- Ectoderm Notes Timeline - Embryonic Week 3 | Carnegie Stages | Stages - scanning electron micrographs | Neural Notes | Neural Crest Notes | Neural Abnormalities | Integumentary Development | Folic Acid and Neural Tube Defects | Week 3 |
- 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
- lateral surface ectoderm
- sensory placodes
- epidermis of skin, hair, glands, ant. pituitary, teeth enamel
- 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
- 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
- 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
Failure for the neural tube to close correctly or completely results in a neural tube defect.
- 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
- 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
- rostral neural tube forms 3 primary brain vesicles (week 4)
- 3 primary vesicles: prosencephalon (forebrain), mesencephalon (midbrain), rhombencephalon (hindbrain)
From the 3 primary vesicles developing to form 5 secondary vesicles
- prosencephalon- telencephalon (endbrain, forms cerebral hemispheres), diencephalon (betweenbrain, forms optic outgrowth)
- 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
- (More? [Notes Chorioid Plexus)
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 stem cells lie in the layer closest to the ventricular space, the ventricular layer
- this layer generates both neuroblasts and glioblasts
Neuroblasts - neurons arise first as neuroblasts and migrate along radial gial, their migration stops at cortical plate. Glioblasts - glia arise later as glioblasts
Both neurons and glia undergo a complex process of growth, differentiation and interaction over a long developmental time period.
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
- Sonic Hedgehog (SHH) - 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)
- 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.
- 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
- Specialized ectodermal "patches" in the head region
- Contribute sensory structures - otic placode (otocyst), nasal placode, lens placode
- Contribute teeth
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 9 SEM
- 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 10 SEM
- 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 11 SEM
- stage 12 (about 26 days) The caudal neuropore takes a day to close Stage 12 SEM
- 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 Stage 13 SEM
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)
Neural Tube Defects (NTD)
Failure of neural tube closure either incorrectly or incomplete
- Dysraphism is the term often used to describe the defective fusion of the neural folds. The position and degree of failure of fusion will result in either embryonic death or a range of different neural defects. The way (mode) in which the human neural tube fuses has been a source of contention. In humans, fusion appears to initiate at multiple sites but the mode is different from that found in many animal species used in developmental studies. (More? Neural Abnormalities)
- severity dependent upon level within the tube and degree of failure
- caudal failure - spina bifida cranial failure - anancephaly
Found that supplementation of maternal diet with folate reduces incidence of NTDs (More? Folic Acid and Neural Tube Defects)
- 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)
In the U.S.A. the Food and Drug Administration in 1996 authorized that all enriched cereal grain products be fortified with folic acid, with optional fortification beginning in March 1996 and mandatory fortification in January 1998. The data below shows the subsequent changes in anencephaly and spina bifida rate over that period.
Critical Periods of Human Development
Exposure to teratogens during these "critical periods" results in specific abnormalities. Critical Periods
- most systems are susceptible during embryonic development (first trimester)
- the earlier the exposure the more severe the effects
- each system has a different critical period
- longest critical periods
- longest developing systems (neural, genital)
- complicated developmental origins (sensory systems)
UNSW Embryology Neural Links
- Neural Lecture 5 2008
- Neural Notes | Stage 13/14 | Stage 22 | Stage 22 Brain | Stage 22 Spinal Cord | Ventricular System | Cerebrospinal Fluid | Week 10 | Fetal | Gliogenesis | Pain | Molecular
- Abnormalities - Abnormalities | Folic Acid and Neural Tube Defects | Critical Periods
- Postnatal - Postnatal Neural | Neural Assessment
- Neural Crest Notes | AbnormalitiesStage 13/14 | Stage 22 | Stage 22 high power | Generation | Migration | Peripheral Ganglia | GIT Enteric | Heart | Molecular | Web Links
- Stages - scanning electron micrographs
- System Notes
- Development Timeline
- 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
- Environmental Health Perspectives Critical Periods of Vulnerability for the Developing Nervous System: Evidence from Humans and Animal Models | PMC: 1637807 | PMID: 10852851
- Journal Development
Neural Development Terms
Only brief descriptions are given below, more complete definitions can be found in the glossary.
- 3DMRI Three-dimensional magnetic resonance imaging. A new technique that allows 3D analysis of embryonic structures. (More? Prenatal Diagnosis - Magnetic Resonance Imaging)
- 3rd ventricle ventricular cavity within the diencephalon.
- 4th ventricle ventricular cavity within the rhombencephalon.
- accessory nerve-
- adenohypophysis anterior pituitary= 3 parts pars distalis, pars intermedia, pars tuberalis
- alar plate afferent, dorsal horns
- anlage (German = primordium, structure or cells which will form a future structure.
- arachnoid- (G.) spider web-like
- basal ganglia-
- basal plate efferent, ventral horns
- brachial plexus mixed spinal nerves innervating the upper limb form a complex meshwork (crossing).
- brain general term for the central nervous system formed from 3 primary vesicles.
- buccopharyngeal membrane (=oral membrane) at cranial (mouth) end of gastrointestinal tract (GIT) where surface ectoderm and GIT endoderm meet. (see also [#cloacal membrane cloacal membrane])
- cauda equina- (=horse's tail) caudal extension of the mature spinal cord.
- central canal lumen, cavity of neural tube within the spinal cord. Space is continuous with ventricular system of the brain.
- cerebral aqueduct ventricular cavity within the mesencephalon.
- cervical flexure most caudal brain flexure (of 3) between spinal cord and rhompencephalon. ( sc-^V^ )
- choroid plexus specialized vascular plexus responsible for secreting ventricular fluid that with further additions becomes cerebrospinal fluid (CSF).
- cloacal membrane at caudal (anal) end of gastrointestinal tract (GIT) where surface ectoderm and GIT endoderm meet forms the openings for GIT, urinary, reproductive tracts. (see also buccopharyngeal membrane)
- cortical plate outer neural tube region which post-mitotic neuroblasts migrate too along radial glia to form adult cortical layers.
- cranial flexure (=midbrain flexure) most cranial brain flexure (of 3) between mesencephalon and prosencephalon. ( sc-^V^ )
- diencephalon the caudal portion of forebrain after it divides into 2 parts in the 5 secondary vesicle brain (week 5). (cavity- 3rd ventricle) Forms the thalmus and other nuclei in the adult brain. (sc-My-Met-Mes-Di-Tel)
- dorsal root ganglia (=spinal ganglia) sensory ganglia derived from the neural crest lying laterally paired and dorsally to the spinal cord (in the embryo found ventral to the spinal cord). Connects centrally with the dorsal horn of the spinal cord.
- dura mater- "tough" (Latin, mater = mother)
- ectoderm the germ layer which form the nervous system from the neural tube and neural crest.
- ependyma epithelia of remnant cells after neurons and glia have been generated and left the ventricular zone
- floorplate early forming thin region of neural tube closest to the notochord.
- ganglia (pl. of ganglion) specialized neural cluster.
- glia supporting, non-neuronal cells of the nervous system. Generated from neuroepithelial stem cells in ventricular zone of neural tube. Form astrocytes, oligodendrocytes.
- glossopharyngeal ganglion-
- grey matter neural regions containing cell bodies (somas) of neurons. In the brain it is the outer layer, in the spinal cord it is inner layer. (see white matter white matter)
- growth factor usually a protein or peptide that will bind a cell membrane receptor and then activates an intracellular signaling pathway. The function of the pathway will be to alter the cell directly or indirectly by changing gene expression. (eg shh)
- hox (=homeobox) family of transcription factors that bind DNA and activate gene expression. Expression of different Hox genes along neural tube defines rostral-caudal axis and segmental levels.
- hydrocephalus abnormality as the result of an imbalance between the rate at which the CSF is being formed and the rate at which the CSF is passing through the arachnoidal villi back into the blood (hydrocephalus rate is a function of the degree of imbalance in these two). Very small imbalance exhibit subtle, if any, symptoms. Large imbalances will have rapidly evolving symptoms of unmistakable import.
- intervertebral foramina-
- isthmus- (G. narrow passage)
- lamina terminalis anterior region of brain where cranial neuropore closes.
- lumbar plexus mixed spinal nerves innervating the lower limb form a complex meshwork (crossing).
- mantle layer layer of cells generated by first neuroblasts migrating from the ventricular zone of the neural tube. Layers are rearranged during development of the brain and spinal cord. (Ven-Man-Mar-CP)
- marginal zone layer of processes from neuroblasts in mantle layer. (Ven-Man-Mar-CP)
- mater (Latin, mater = mother)
- meninges mesenchyme surrounding neural tube forms 3 layer (Dura-, pia-, arachnoid- mater) connective tissue sheath of nervous system. (D-P-A-cns)
- mesencephalon (=midbrain), the middle portion of the 3 primary vesicle brain (week 4). (sc-R-M-P)
- metencephalon the cranial portion of hindbrain after it divides into 2 parts in the 5 secondary vesicle brain (week 5). Forms the pons and cerebellum in the adult brain. (sc-My-Met-Mes-Di-Tel)
- myelencephalon the caudal portion of hindbrain after it divides into 2 parts in the 5 secondary vesicle brain (week 5). Forms the medulla in the adult brain. (sc-My-Met-Mes-Di-Tel)
- neural tube neural plate region of ectoderm pinched off to form hollow ectodermal tube above notochord in mesoderm.
- neural tube defect (NTD) any developmental abnormality that affects neural tube development. Commonly failure of neural tube closure.
- neuroblast undifferentiated neuron found in ventricular layer of neural tube.
- neurohypophysis (=posterior pituitary=pas nervosa)
- neuron The cellur "unit" of the nervous system, transmitting signals between neurons and other cells. The post-mitotic cells generated from neuroepithelial stem cells (neuroblasts) in ventricular zone of neural tube.
- neuropore opening at either end of neural tube: cranial=rostral=anterior, caudal=posterior. The cranial neuropore closes (day 25) approx. 2 days (human) before caudal.
- notochord rod of cells lying in mesoderm layer ventral to the neural tube, induces neural tube and secretes sonic hedgehog which "ventralizes" the neural tube.
- olfactory bulb (=cranial nerve I, CN I) bipolar neurons from nasal epithelium project axons through cribiform palate into olfactory bulb of the brain.
- optic cup-
- optic nerve (=cranial nerve II, CN II) retinal ganglion neurons project from the retina as a tract into the brain (at the level of the diencephalon).
- otocyst (=otic vesicle) sensory [#placode placode] which sinks into mesoderm to form spherical vesicle (stage 13/14 embryo) that will form components of the inner ear.
- pars (L. part of)
- pharyngeal arches (=branchial arches, Gk. gill) form structures of the head. Six arches form but only 4 form any structures. Each arch has a pouch, membrane and cleft.
- pharynx uppermost end of GIT, beginning at the buccopharyngeal membrane and at the level of the pharyngeal arches.
- pia mater-
- placode specialized regions of ectoderm which form components of the sensory apparatus.
- pontine flexure middle brain flexure (of 3) between cervical and cranial flexure in opposite direction, also generates thin roof of rhombencephalon and divides it into myelencephalon and metencephalon. ( sc-^V^ )
- prosencephalon (=forebrain), the most cranial portion of the 3 primary vesicle brain (week 4). (sc-R-M-P)
- Rathke's pouch a portion of the roof of the pharynx pushes upward towards the floor of the brain forming the anterior pituirary (adenohypophysis, pars distalis, pars tuberalis pars intermedia). Where it meets a portion of the brain pushing downward forming the posterior pituitary (neurohypophysis, pars nervosa). Rathke's pouch eventually looses its connection with the pharynx. (Martin Heinrich Rathke 1973-1860, embryologist and anatomist)
- rhombencephalon (=hindbrain), the most caudal portion of the 3 primary vesicle brain (week 4). (sc-R-M-P)
- roofplate early forming thin region of neural tube closest to the overlying ectoderm.
- spinal cord caudal end of neural tube that does not contribute to brain. Note: the process of secondary neuralation contributes the caudal end of the spinal cord.
- spinal ganglia (=dorsal root ganglia, drg) sensory ganglia derived from the neural crest lying laterally paired and dorsally to the spinal cord (in the embryo found ventral to the spinal cord). Connects centrally with the dorsal horn of the spinal cord.
- spinal nerve mixed nerve (motor and sensory) arising as latera pairs at each vertebral segmental level.
- sonic hedgehog (=shh) secreted growth factor that binds patched (ptc) receptor on cell membrane. SHH function is different for different tissues in the embryo. In the nervous system, it is secreted by the notochord, ventralizes the neural tube, inducing the floor plate and motor neurons.
- sulcus (L. furrow) groove
- sulcus limitans longitudinal lateral groove in neural tube approx. midway between roofplate and floorplate. Groove divides alar (dorsal) and basal (ventral) plate regions.
- sympathetic ganglia-
- telencephalon the cranial portion of forebrain after it divides into 2 parts in the 5 secondary vesicle brain (week 5). (cavity- lateral ventricles and some of 3rd ventricle) Forms the cerebral hemispheres in the adult brain. (sc-My-Met-Mes-Di-Tel)
- thalamus (G. thalamos= bedchamber) cns nucleus, lateral to 3rd ventricle, paired (pl thalami).
- transcription factor a factor (protein or protein with steroid) that binds to DNA to alter gene expression, usually to activate. (eg steroid hormone+receptor, Retinoic acid+Receptor, Hox, Pax, Lim, Nkx-2.2)
- trigeminal ganglion (=cranial nerve V, CN V) first arch ganglion, very large and has 3 portions.
- vagal ganglion- (=cranial nerve X, CN X) fourth and sixth arch ganglion, innervates the viscera and heart.
- ventricles the fluid-filled interconnected cavity system with the brain. Fluid (cerebrospinal fluid, CSF) is generated by the specialized vascular network, the choroid plexus. The ventricles are directly connected to the spinal canal (within the spinal cord).
- ventricular zone Neuroepithelial cell layer of neural tube closest to lumen. Neuroepithelial cells generate neurons, glia and ependymal cells. (Ven-Man-Mar-CP)
- vestibulocochlear nerve (=cranial nerve VIII, CN VIII, also called statoacoustic)
- white matter neural regions containing processes (axons) of neurons. In the brain it is the inner layer, in the spinal cord it is outer layer. (see grey matter)
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