BIO 185: Topics in Biology – Fall 2003
Developmental Biology – Outline 3, Part 1
III. Development of the Ectoderm: In the last section we talked about the
formation of the epiblast and then the migration of huge numbers of cells through
the primitive streak to adopt endodermal and mesodermal fates. In addition the
regression of Henson’s Node left behind the notochord in the mesoderm. But what
of those that don’t migrate into the blastocoel? Are they left to pine for a greater
fate of travel and adventure? In fact, those cells that remain at the dorsal surface
make up the ectodermal layer (or plate) and life has great things in store for most of
them. Neurons! From the simple left-overs of the epiblast to the source of thought,
emotion and systemic control of the entire organism. We’ll also look at the fates of
other cells from the ectoderm as they become components of the skin and yet others,
those of the neural crest, that become an amazing diversity of cells. This is a good
time to be last – your descendents shall rule their world…
A. Neurulation: By definition: the formation of the neural tube from the cells of the
epiblast. The neural tube then gives rise to the central nervous system, the brain and
spinal cord. Obviously restricted to the family Chordata, the process involves formation
of the neural tube, its differentiation along its length and the differentiation of central
nervous system neurons. Some very sophisticated neuronal tissues have developed over
the millennia and we will look at the example of the vertebrate eye.
1. The Signals Which Differentiate Neural Cells (p. 391)
a. A Few Good Words
1. Specification and Determination
2. Competence
3. Terminal Differentiation
b. A Few Good Guesses
1. Competence is established by fibroblast growth factors (FGFs)
2. Specification is due to chordin, noggin and follistatin
3. Determination is accomplished by insulin-like growth factors (IGFs)
4. Lateral regions of the epiblast are non-neuronal
a. These cells make Wnts and FGFs are inhibited by Wnts
2. Formation of the Neural Tube (p. 393)
a. Terminology:
1. Primary Neurulation – the anterior portion of the neural plate
invaginates and curls up to form a tube.
2. Secondary Neurulation – the posterior portion coalesces as a solid cord
from surrounding mesenchymal cells and then hollows out into a tube.
b. Formation of the Neural Plate and the Presumptive Epidermis.
1. Signals to ectoderm cells come from mesoderm and endoderm below.
2. The cells at the center of the ectoderm become columnar and neural.
3. As the embryo elongates, so does the neural plate and epidermis.
c. Formation of the Neural Folds and the Neural Groove.
1. Folds result from the formation of two hinge regions.
a. Medial Hinge Point forms along notochord
b. Dorsolateral Hinge Points form along neuro-epidermal border
2. Hinging is cytoskeletal change in neural cells and epidermal expansion
a. Cell wedging is due to microtubules forcing increased height
and microfilaments pinching in the apical ends of the cells.
b. Inward folding is forced by growth of epidermal cells.
d. Closure of the Neural Tube.
1. As the two folds contact, they adhere and merge.
a. Around this time the neural crest cells migrate away.
2. This process occurs generally anterior to posterior.
a. Tube is closing up front before gastrulation is finished in back
3. Regions close at different times and at different rates – 1 in 500 fail!
a. Spina bifida is a failure of the posterior neural tube to close.
b. Anencephaly is a failure of the anterior tube to close.
c. Craniorachischisis is complete failure to close.
d. Folic acid and unexplained seasonal effects are related.
e. Secondary Neurulation in the Posterior of the Embryo.
1. Individually migrating mesenchymal cells condense.
a. Even before Hensen’s Node forms a notochord in the region.
2. Form a solid cord underneath the surface ectoderm.
3. This solid cord is then hollowed out (apoptosis?) into neural tube.
4. Spina bifida is the most common spinal cord defect – hmmm…
3. Differentiation of the Neural Tube (p. 398)
a. The Three Levels of Neural Differentiation
1. Anatomically the tube bulges and constricts to form the various
regions of the brain and spinal cord.
2. At the tissue level the cells rearrange to form layered structures.
3. At the cell level the various neurons and glia differentiate.
4. The chick brain expands 30-fold in 3 days (E3-E5).
a. Mostly due to fluid pressure in lumen – drives differentiation.
b. Constrictions are due to expansion of non-neural tissues.
1. Separates brain from cord.
b. Along the Anterior-Posterior Axis
1. The first 3 anterior bulges start before posterior neural tube is done.
a. Proencephalon will give rise to the forebrain.
b. Mesencephalon will give rise to the midbrain.
c. Rhombencephalon will give rise to the hindbrain.
2. The secondary anterior bulges start around finish at the back end.
a. The proencephalon divides into cerebrum and visual systems.
1. The optic vesicles extend laterally from.
2. The telencephalon will become cerebral hemispheres.
3. The diencephalon gives rise to visual systems.
b. The mesencephalon doesn’t subdivide – stays the midbrain.
c. The rhombencephalon starts with two bulges.
1. The myelencephalon gives the medulla oblongata and
the metencephalon gives rise to the cerebellum
2. Keeps forming bulges (rhombomeres) where specific
nerve connections form – differentiation boundaries.
3. Anterior-Posterior Patterning is Controlled by Hox Gene Expression.
b. The Dorsal-Ventral Axis
1. Both brain and spinal cord have significant dorsal-ventral structure.
a. Cerebrum has six layers.
b. Spinal cord has input, output, interneurons.
2. Two sources of information regulate dorsal-ventral patterning.
a. Ventral signal is sonic hedgehog from the notochord.
b. Dorsal signal is TGF- family proteins from the epidermis.
3. Sonic hedgehog induces medial hinge cells to become “floor plate”.
a. Yet another secondary “organizer”.
4. TGF- family proteins induces closure sites to become “roof plate”.
a. Yet another secondary “organizer”.
4. Specification and Differentiation of Neurons (p. 410, 442)
a. Neuronal Development.
1. Induction and Patterning – Progressive Specification
2. Birth and Migration of Neurons and Glia.
a. We have 100 billion neurons and a trillion glial cells
b. Ependymal cells line the inner tube and give rise to both
3. Dendrite Development.
a. Average cortical neuron makes 10,000 connections
b. At birth our neurons have a few or no dendrites
1. The first year sees nearly all connections made!
4. Axon Development.
a. Growth cone and path finding – cell migration on a leash
b. Actin at the tips and tubulin giving extension
1. Remember hinge cells?
c. Myelination
1. Cell wrapping for conduction
2. Oligodendrocytes in CNS, Schwann cells in PNS
3. Multiple sclerosis is a disease of myelination
5. Synaptogenesis
a. Structure formation
b. Neurotransmitter development
1. Transcriptional control of enzyme pathway expression
b. Progressive Specification of Neurons.
1. Specification of Neural Fate vs. Glial (or Epidermal).
a. Occurs through the delta-notch pathway.
2. Specification of Neuronal Type.
a. Occurs due to position in neural tube on cell “birthday”.
1. Cells of ventrolateral margin become motor neurons
2. Cells from dorsal position become interneurons
b. Position relative to the notocord and the floor and roof plates
1. Motor neurons need sonic two hedgehog signals
3. Target Specificity.
a. Occurs due to order of cell “birthday”.
b. First cells born differentiate and secrete retinoids.
c. The next wave must migrate through them.
1. The signal changes lim-protein expression
2. Transcription factors related to hox-proteins
d. Before axon is sent out it knows its target
1. First wave (medial cells) innervates ventral muscle
2. Second wave (lateral cells) innervates dorsal muscle
c. Axonal Guidance.
1. Selection of the Road.
a. Permissive cell adhesion to extracellular matrix
1. Laminin guides growth cones
2. Fibronectin guides cell bodies
b. Repulsive adhesion by eph/ephrins and semaphorins
c. Permissive and repulsive soluble agents - netrins
d. Combinations are the reality – remember summation!
2. Selection of the Town.
a. Permissive axon adhesion by eph/ephrins and cadherins.
b. Permissive dendrite adhesion by semaphorins.
c. Chemotactic agents – neurotrophins.
3. Selection of the Address.
a. Competative synaptic finalization
1. All junctions start with two or more connections
2. Low synaptic activity “losers” move on, or...
b. Differential survival – apoptosis is common.
d. Behaviors and Neuronal Development
1. Hard-Wired Behaviors
a. E19 chick’s heart rate increases when they hear a distress call
b. Just hatched chick hides when exposed to hawk shadow
2. Neuronal Plasticity.
a. Experiences change patterns.
b. Retinal ganglion axons compete again when eyes open.
B. Development of the S kin: The skin is a complex organ made up of three layers:
the ectodermally derived epidermis (the surface that you think of as skin) and beneath
that the mesodermally derived dermis and subdermal connective tissue. The epidermis
itself is complex, consisting of cells in a variety of stages – actively dividing,
differentiating, committing suicide and even hanging around after they’re dead! There are
also many specialized cells and structures in the skin that are derived from the same stem
cells, including hair (feathers and scales), sebaceous and sweat glands, mammary glands
and teeth. Surprisingly, the skin is a very interesting place!
1. The Origins of the Epidermis Proper (p. 416)
a. After neurulation there is a single cell layer remaining in ectoderm.
b. This layer soon forms a second layer.
1. The inner layer will go on to form the epidermis.
2. The outer layer, or periderm, is temporary covering.
a. It is shed in the embryo as soon as the inner layer gets going.
c. The inner layer, or basal layer, is a germinal epithelium (like ependymal cells).
1. Gives rise to all cells of the epidermis
2. The first step down the pathway is the formation of spinous cells.
a. Forms a second dividing layer on top of the basal cell layer.
b. The two layers combined are the epidermal stem cells.
c. Called the Malpighian layer.
3. The second step is the formation of granular cells.
a. Called that because they store granules of keratin.
b. These cells have withdrawn from the cell cycle.
c. They continue to make keratin and migrate outward.
4. Maturing granular cells become keratinocytes.
a. Make huge amounts of keratin and cell-cell connections.
b. As they mature they quit supporting themselves metabolically.
c. When they die they hang around in the cornified layer.
5. An interesting event is the migration of neural crest cells into the
epidermis to form melanocytes, the melaning producers of the skin.
a. They set up shop and pass melanosomes to keratinocytes.
b. The cornified layer still has fading melanosomes at the end.
d. This process continues from neurulation until death.
1. In the normal adult human a Malpighian cell is born, takes eight weeks
to reach the cornified layer and then two weeks to be sloughed off.
2. Psoriasis is linked to this process through TGF-.
a. TGF- stimulates basal cell division.
b. Overexpression leads to rapid turnover and dead keratinocytes
last only two days in the cornified layer.
2. The Origins of Specialized Cells and Cutaneous Appendages (p. 418)
a. All of these structures form from basal cells in the epidermis.
b. Basal cells are induced by the dermis to differentiate down a new path.
1. Mesodermal dermis interacts with ectodermal epidermis.
a. Induction between cell types is a common theme.
2. Placode formation
a. Fibroblasts of dermis condense under control of Wnt’s.
b. Signal basal cells by FGF 10 to form columnar epithelium,
divide and then growing placode sinks into upper dermal layer.
3. Most of what we know is known about hair formation (p. 419)
a. Probably somewhat similar for other structures.
b. Fibroblasts condense further to form a dermal papilla.
1. Node of cells under sunken epidermal cells.
2. This turns the structure into a follicle.
c. Drives a further increase in the rate of division in basal cells.
1. Promoted by autocrine sonic hedgehog.
2. Also release BMP’s to stop neighbors from joining.
d. Epidermal cells differentiate into keratinocytes of hair shaft.
1. These are actually dead cells like cornified layer.
2. Three types of hair shaft.
a. Lanugo – embryonic, thin and short.
b. Vellus – preadolescent, silky and short
c. Terminal shaft – long, thick and pigmented
d. Male Pattern Baldness: follicles make vellus
e. Follicular bulb develops in basal epithelia.
1. Basal cell stem cells to regenerate follicle.
2. Melanoblast stem cells to regenerate color.
f. Sebaceous bulb develops in basal epithelia.
1. Secrete sebum onto the shaft and skin.