Embryology Part 2 Flashcards
What is the notochord?
Thickened region in mesoderm important in controlling specification of surrounding cells.
Signalling centre along centre
Important in development of nervous system
What is the Paraxial Mesoderm and what will it form?
Closest to the axis, where development of the vertebral column (notochord) point in the mesoderm.
Will form the somites which forms the Dorsal somites, leading to dermomyotome (dermis/muscles of back,) and Ventral/Medial Somites leading to the sclerotome (vertebrae and ribs)
What are the layers of the mesoderm moving from the notochord, laterally?
Notochord Paraxial Mesoderm Intermediate Mesoderm Lateral Plate Mesoderm Extraembryonic Mesoderm
What regions in the embryo do not contain mesoderm? What parts of the body will these regions form?
Oropharyngeal membrane (will develop to form mouth opening) Cloacal Membrane (will form anus) Don't require muscle for these areas, so pointless building up structures to break them down
How long does the formation of the 3 regions of mesoderm take?
4 days
What is the somite?
Building block of the muscle
What does the Intermediate Mesoderm form?
Genitourinary system
How does the Lateral Plate Mesoderm (and surrounding space) change with embryological development?
The LPM forms 2 layers which become split by the intraembryonic coelom.
The 2 layers are; Parietal aka somatic (superior) and Visceral aka splanchnic (inferior)
What germ layer forms the following smooth muscle components of the body- pupils, mammary, and sweat glands?
Ectoderm
What part of the body is formed from the Visceral (Splanchnic) Lateral plate mesoderm?
Gut and derivative smooth layers from the visceral layer surrounding the gut tube
Cardiac muscle from visceral layer surrounding heart tube
In what order, and when, does somite formation occur?
Form in pairs from head of embryo towards the tail end
Cranio-caudal sequence
Day 20 (weeks 3-5)
How is somitogenesis controlled?
Signals are turned on that help stimulate mesenchymal (loose cells) migration and tightening to epithelial like cells. This aids in the formation of the neural tube.
Notochord influences somite formation
Regulation via Notch, Wnt, and FGF
What genes control somitogenesis and how do levels of gene expression change during this process?
Notch- high levels initiate somite development, and then quickly decreases, moves head to tail
FGF8 Family- increase as notch decreases, moves tail to head
Wnt - Help process along
How do genes aid in somitogenesis?
They tell cells to switch between permissive and non-permissive state in constant timed fashion.
What happens to somites once they’ve formed?
They will go on to differentiate into the sclerotome (vertebrae and ribs) and dermomyotome (dermis and muscle of back)
When is somitogenesis complete, and how many pairs of somites are created?
Begins day 20, complete by end of 5th week
42-44 pairs
What is a somite?
Cells of paraxial mesoderm origin that help form the skeletal muscles and skeleton.
What happens to the somites once formed?
Starts to form different cell structure with cell proliferation
Start to differentiate
-> ventral/medial undergo epithelial to mesenchymal transition, forming sclerotome
-> dorsal cells form dermomyotome
What is the sclerotome?
Ventral somite cells that undergo epithelial to mesenchymal transitions (allowing them to migrate again)
Sclerotome helps form the vertebrae and ribs
What does the dermomyotome form?
Splits to form:
Dermatome- forms dermis of back
Myotome- forms muscles
What are the muscle cell precursors, and what stimulates the differentiation of the precursors into muscle cells?
Myoblasts
Myogenin stimulates differentiation of myoblasts into primary myotubes (they will align and fuse), and finally into myocytes (mature muscle cells)
MyoD and Myf5 are transcription factors that activate muscle specific genes and mediate differentiation of myoblast precursor cells into myoblasts.
What factors regulate the development of muscle during embryological development?
MYOD
MYF5
These transcription factors activate muscle-specific genes and enable differentiation of myogenic precursor cells in the dermomyotome into myoblasts
Where is MyoD (myoblast determination protein 1) found and how is it turned on?
Locally acting WNT proteins (activate) and BMP (inhibitory) will activate the MYOD at the edge of the dermomyotome.
MyoD and Myf5 enable differentiation of myogenic precursor cells in dermomyotomes into myoblasts.
How do you stimulate the formation of the dermatome from the dermomyotome?
The lateral plate mesoderm also produce WNT and BMP that can stimulate dermatome formation (as the WNT and BMP released from neural tube and notochord cannot move far enough to reach further parts of the dermomyotome)
What does the notochord release that acts on the sclerotome?
Sonic hedgehog and noggin will stimulate the sclerotome to form bone.
What is the WNT family?
Signalling molecules that control biological and developmental processes.
During development aid in body axis patterning, cell fate specification, cell proliferation and migration
What is BMP?
Growth factor/cytokine family.
Control tissue architecture and induce bone/cartilage formation during development.
Dysregulated BMP signalling may lead to cancer
What is sonic hedgehog?
Acts as a morphogen (molecule that diffuses to form concentration gradient and has different effects on cells of the embryo)
Induces sclerotome formation of somites from ventral/ medial portion paraxial mesoderm
What is FGF?
Fibroblast Growth Factor-Cell signalling growth factors that activates cell surface receptors.
Often acts as mitogen
Stimulates WNT signalling.
Role in mesoderm induction and limb development
What is notch?
Transmembrane proteins that control cell fate decisions.
Involved in regulation of somitogenesis
How do we know that MYF5 and MYOD are important in skeletal muscle formation?
Test looking at mice-knock out and gain of function tests for the genes separately and together showed if both are mutated, muscle wont form, but individual knock out isn’t fatal.
Where does smooth muscle originate from? Include 2 exceptions.
Splanchnic mesoderm
-except for ciliary muscle, sphincter pupillae of eye (ectoderm)
What aids in smooth muscle differentiation during development?
Serum Response Factors (SRF) stimulates differentiation
SRF is upregulated by kinase phosphorylation pathways, and enhanced by myocardin/ myocardin-related transcription factors
What genes are important in skeletal muscle formation?
MYOD
Myf5
Myogenin
Where does Cardiac Muscle originate and how does it develop?
Splanchnic lateral plate mesoderm
Develops as tube structure, and then bends to form chambers
Myoblasts adhere together to form intercalated discs
MyoD is not involved in early cardiac muscle development
What genes are involved in specification of cardiac muscle?
Tinman gene
Which region of mesoderm will form the body wall of the developing embryo?
Somatic / Parietal Lateral Plate Mesoderm
The intraembryonic coelom is a cavity that forms within the ______ mesoderm.
Lateral Plate
What does the sclerotome form?
Ribs and vertebrae
What are the two types of folding that occur during development, and when?
Lateral and caudal-cephalic folding happen between 23-28 days
What germ layer forms the neural tube?
Ectoderm
What is the Mantel Zone, where is it found during development, and what does it give rise to?
Found proximal to the neural cavity within the neural tube
Neural Blast cells are replicating here, and this section gives rise to grey matter
What is the Marginal Zone, where is it found during development, and what does it give rise to?
Zone at periphery of neural tube
Processes growing out of neural blast cells of mantel zone are here.
Gives rise to white matter
What germ layer forms the amnion?
Ectoderm
During day 23 of development, how does the somatic lateral plate mesoderm change?
It will move to combine with the somatic LPM on the other side of the embryo, encircling the splanchnic mesoderm and endoderm
How does intramembranous ossification occur?
Mesenchymal Stem cells undergo condensation/proliferation to form osteoprogenitor cells.
Osteoprogenitor cells differentiate into osteoblasts.
Osteoblasts secrete bone matrix, forming bone
When does limb formation occur during development?
Weeks 4-8
week 4=4 limbs developing for 4 weeks!
What is the Mesenchyme?
A type of connective tissue found during development of the embryo.
Arises from mesoderm (dorsolateral somites , therefore paraxial mesoderm).
Contains loosely packed, highly migratory, non-specialized cells
What are limb buds?
Small ridges that begin developing at week 4 that give rise to our limbs
Forming from ventrolateral wall of embryo, using ectoderm and mesoderm (dorsolateral mesoderm cells of somites, therefore paraxial mesoderm) germ layers
Some parts of the somatic lateral plate mesoderm will contribute as well.
Which limb bud develops first?
Upper limbs
What is the first sign of limb bud formation?
Condensation of mesenchyme near where the limbs will develop
What do limb buds consist of in terms of cell make-up?
Have mesenchymal core from dorsolateral mesoderm cells of paraxial somites, as well as contributions from somatic layer of lateral plate mesoderm, covered in cuboidal ectoderm cells.
Ectoderm at the distal border thickens to form apical ectodermal ridge
What is the apical ectodermal ridge?
Inductive signalling center that signals to mesoderm and tells it to remain undifferentiated, as the limb grows, cells further away will begin to differentiate into cartilage and muscle of upper limb.
Found near the distal end and acts as an axis as it splits limb into dorsal and ventral side.
What portion of the germ line forms the limbs?
Mesoderm- Paraxial (dorsolateral somite cells of mesenchyme) as well as some contributions from somatic portion of lateral plate mesoderm
Ectoderm form outer layer
What is FGF10 and what secretes it?
Cytokine that initiates the outgrowth of the limb.
Secreted by lateral plate mesoderm
High mitogenic activity
What is radical fringe?
Signalling molecule expressed by dorsal ectoderm- dorsal side of AER.
It has impact on dorsal mesoderm
What is the engrailed-1?
Transcription factor expressed by ventral ectoderm
It represses expression of radical fringe
What is SER2?
Signalling molecule found between the dorsal and ventral sides of the limbs during development
What prevents differentiation of cells at the distal ends of limbs during limb development?
FGF4 and 8 are essential for this.
Knockouts of this will prevent upper limb development
What signal begins the differentiation of cells during limb development?
Retinoic Acid at the proximal end begins differentiation into the proximal components
What signalling molecules establish dorsal/ventral aspects of limbs?
Radical fringe, Engrailed-1, and SER2 control the location of the AER, and thus establish dorsal (radical fringe presence) and ventral (engrailed-1 suppression of radical fringe) sections of the arm
What factors designate upper vs lower limb?
TBX5 expressed in upper limbs
TBX4 expressed in hind limbs
Why is the ectoderm so important for limb development?
It establishes the AER which prevents differentiation of mesoderm cells as the limb grows.
This allows for very organized differentiation of the somatic lateral plate mesoderm cells
What occurs in terms of limb development at week 6?
Terminal portions of buds become flattened
Narrowing occurs which results in segmentation into 3 main parts; hand (autopod), forearm (zeugopod), arm (stylopod)
What are the 3 components of the upper limb, moving proximalodistally?
arm (stylopod)
forearm (zeugopod)
hand (autopod)
What are HOX genes and how do they relate to limb development?
Expressed in overlapping patterns along the upper limb, and control development of different portions of the limb.
What are the corresponding HOX genes with portions of the arm?
9- Scapula all the way to distal phalanges
10- Femur to distal phalanges
11- Proximal Ulna to distal phalanges
12- Distal row of carpals to distal phalanges
13- Metacarpals to distal phalanges
What is polydactylyl?
Genetic recessive trait in Hox, Sonic hedgehog, or Wnt genes that results in extra digits.
How do fingers develop?
Apoptosis occurs at the apical epidermal ridge, leaving 5 parts which control the outgrowth of the 5 digits.
While this happens, mesenchyme starts to condense to form cartilage hand and foot plates
Developed by day 56
What is more important in limb development, the mesoderm or ectoderm? How do you know?
The mesoderm
Experiments involving ectoderm and/or mesoderm removal/relocation demonstrates that the mesoderm is more important and determines the development or lack thereof
Mesoderm also dictates clock specifications for limb development
What happens in week 7 of limb development?
Rotation occurs along coronal to the parasaggital plane, and then along long axis.
Upper arm rotates 90 degrees laterally so elbow points backwards, and thigh rotates 90 degrees medially so knee faces forward.
What are the stages of bone formation during development? Include weeks.
Week 4- Limb buds become visible, loose mesenchyme begins to condense and differentiate into chondrocytes (driven by BMPs)
Week 6- Hyaline cartilage models can be seen, flattening of terminal bud to form hand/footplates
Week 7- Limb bud rotations
Week 8- Ossification begins
Week 12- Primary ossification centres are found in long bones
Birth- Secondary ossification centres appear, diaphysis should be ossified, epiphyses still cartilaginous
What part of the bone forms first during endochondral ossification?
The bone collar at the diaphysis of the cartilage
What forms of growth occurs in long bones up until puberty?
Interstitial growth increases length at metaphyseal plates
Appositional growth increases the diameter
Both use endochondral ossification
What complications are associate with congenital limb issues?
Craniofacial, cardiac, and /or genito-urinary
When can achondroplasia be diagnosed?
Around 20 weeks, using an ultrasound to measure the length of long bones
What is achondroplasia?
An autosomal dominant condition (overexpression of FGF3 mutation- commonly sporadic) impacting bone growth that affects endochondral ossification via cartilage.
Particularly affects the long bones of the arms and legs.
Can cause problems with breathing, spine curvature, and walking
What does FGFR3 typically do?
It inhibits chondrocyte proliferation and differentiation
Hyperactive FGFR3 means increased inhibition
How does FGFR3 relate to achondroplasia?
FGFR3 is mutated to be hyperactive, resulting in increased inhibition chondrocyte proliferation/differentiation.
This means epiphyses cannot grow correctly
What can be used to treat achondroplasia?
Limb lengthening surgery (painful and no guarantee)
Vosoritide drug which lengthens limbs
Gene editing- CRISPR/Cas9 correcting FGFR3 mutation is in the works
During the development of muscle groups in the limb bud, dorsal portions develop mainly into which groups?
Extensors, pronators and adductors
How do joints form during embryological development?
Wnt14 induces increased chondrocyte proliferation, density, differentiation, then death.
The areas with arrested chondrogenesis form joints
