S3: Musculoskeletal Development II - Muscle and Innervation Flashcards
How do myoblasts from somites travel to limb buds?
Myoblasts (from somites) are attracted by paracrine signals produced by the limb bud and migrate towards them. As the myoblasts migrate into the limb buds they also generate trophic factors that will attract their own innervation.
What does the early limb bud consist of?
The early limb bud consists of an ectodermal jacket surrounding a mesenchymal core.
What develops from limb buds, myotomes and spinal nerves?
- Skeleton (including girdles) from limb bud mesenchyme
- Tendons, ligaments, fascia, dermis also from limb bud mesenchyme
- Muscles from myotome of somites (attracted and migrate to limb buds)
- Nerves from spinal nerves
What happens to myoblasts after they migrate the limb buds?
· Myoblast population then divides into 2 populations:
- dorsal – extensor muscles of limb
- ventral – flexor muscles of limb
What establishes the 3 planes of asymmetries along limb axes?
They are established by molecular signals released by specific parts of the limb buds as it develops. The sources of signals are apical ectodermal ridge, dorsal ectoderm and zone of polarising activity. These three signalling centres interact with each other and the signals they produce influence the activity of each other.
- Anterior-posterior polarity in the limb bud is due to ZPA.
- Proximal-distal polarity is due to apical ectodermal ridge.
- Dorsal-ventral polarity is due to dorsal ectoderm.
Describe zone of polarising activity and the anterior posterior axis grafting experiments in chicks
Normal: limb buds in chick would develop normal wing (with lots of asymmetries along anterior and posterior axis)
Scientists took a piece of tissue from donor limb bud where zone of polarising activity and grafted it into a host embryo in anterior portion of limb bud. The result was that there was double posterior duplication (mirror image).
Brief overview of the steps myotomes take to turn into muscles
The cells from the somite called myotomes need to migrate out of somite to the locating where muscles are formed and they need to differentiate into myofibers that will be assembled in fascicles and eventually differentiate into muscles.
What is the sequence of myotome to myofibre?
- The somite myotome are specified cells (MCPs).
- MCPs migrate to muscle location and proliferate into myoblasts.
- Initial myoblast fusion forms the primary myotube.
- Further myoblast proliferation and fusion forms the secondary myotube.
- Innervation and expression of contractile proteins makes the secondary myotube turn into a myofibre.
What drives the process of myotome to myofibre?
Cascade of Transcription factors
Describe satellite cells
- Not all the myoblasts fuse into myotubes. These cels are satellite cells and are essential for the muscles to grow postnatally and to regenerate.
- Satellite cells are muscle resident stem cells that are attached to the muscle fibre along muscles.
- They express Pax7.
- They give rise to muscle when aggravated.
- The molecular sequence of differentiation recapitulates muscle development.
Describe the Mature NMJ
- Each muscle fibre is innervated by just one motor neurone.
- At presynaptic side the terminal is full of vesicles containing the neurotransmitter acetyl choline
- Postsynaptically the membrane is extremely folded and at the ridges of the folds, there are clusters of very concentrated acetyl choline receptors. At the base of the folds there are ion channels.
- The basal lamina is between pre and post synaptic domain.
Describe the development of the NMJ
As the muscle fibre diffrentiates, the growth cone several axons approach and make contact with the muscle fibre surface. As they make contact, highly specialised extracellular matrix becomes deposited. The axons make more connects and Ach receptors become concentrated. At this point, axons start to generate action potentials. This leads to an ‘ competition ‘ between axons. Eventually, only one of the axons will maintain its synaptic connection while the other will regress. Once this happens, the NMJ becomes highly elaborate and acquires all its characteristics.
- The growth cone is attracted by the high density of AChR clusters.
What 2 molecular substances are required for the formation of NMJ?
- Very high density of Ach receptors on myofibril surface are needed.
- Secretion of agrin.
Describe function and mechanism of Agrin and Musk for NMJ development
- Regions with high expression of myogenic factors and postsynaptic molecules, such as AChRs, are seen on the myofiber prior to innervation.
- The growth cone is attracted to these sites and secretes Agrin.
- Agrin is essential for the formation of extracellular matrix
- Agrin: heparan sulfate proteoglycan that acts as a signal binding to Musk , a transmembrane tyrosine kinase receptor on the myofiber.
- Agrin accumulates at the NMJ and binds to Musk. Musk levels increase in the NMJ region (positive feedback loop)
- Agrin and Musk stabilise AChR clustering and promote maturation of the NMJ.
Describe Ossification problems - Anchondroplastic dwarfism
- Literally means “without cartilage formation.”
- Occurs when there are defects in FGF signalling or issues in chondrocyte proliferation.
- The problem is not in cartilage formation, but in converting it to bone.
- Results in shortened limb bones due to premature closure of epiphyseal growth plates – and termination of bone growth.
