Lecture 3 - Neural Induction and Pattern Formation Flashcards
What are the general/major structures of human embryonic and adult brain?
Embryo at one month - Embryo at five weeks - Adult
Forebrain - Telencephalon - Cerebrum (cerebral hemispheres; includes cerebral cortex, white matter, basal nuclei)
Forebrain - Diencephalon - Diencephalon (thalamus, hypothalamus, epithalamus)
Midbrain - Mesencephalon - Midbrain (part of brainstem)
Hindbrain - Metencephalon - Pons (part of brainstem), cerebellum
Hindbrain - Myelencephalon - Medulla oblongata (part of brainstem)
What are the key concepts in neural induction and CNS patterning?
The central nervous system (CNS) develops from an epithelial ‘plate’ of ectoderm cells, triggered by molecular signals from the early midline mesoderm (neural induction).
Several localized signalling centres, placed both outside and within the neural tube, coordinate patterning and regional differentiation of the nervous system.
The centres establish gradients and counter gradients of a variety of morphogens that generate a patterned array of different nerve cell types.
Morphogen gradients generate discrete changes in the populations of transcription factors expressed by individual cells. Morphogens have different effects according to the differentiation state of the cells they influence.
Diversity in the nervous system arises from the action of a small set of morphogen families expressed in the right place at the right time, such as: Shh, retinoic acid (RA), Wnts, BMPs/TGFßs and FGFs.
What is gastrulation?
What occurs during gastrulation?
Gastrulation - making the three
germ layer and subsequently the
induction of a neural tube
During early vertebrate embryonic development, cells become arranged to form three primary germ layers that give rise to all adult tissues during Gastrulation:
- Prospective endoderm is brought inside the embryo
- Prospective ectoderm covers the surface of the embryo
- Prospective mesoderm is positioned between these two. For Chordates (which include the Vertebrates), a flexible rod-like structure of mesodermal cells that is the principal longitudinal structural element, called notochord, is formed during gastrulation
What acts as an organiser of gastrulation in vertebrates?
The dorsal lip of the blastopore of the embryo
What experiments were used to demonstrate the role of the dorsal lip of the gastulating embryo in neural induction?
A. Transplanted dorsal lip could induce the formation of a double axis in the new host embryo - the dorsal lip’s sufficiency in neural induction.
B. Injection of extracted mRNA from the dorsal lip into irradiated Xenopus embryos rescued neural induction and overall development demonstrating there is a genetic basis of neural induction.
C. Establishment of cDNA libraries from extracted dorsal lip mRNA identified candidate genes that may be responsible for neural induction. One such candidate gene, noggin, is sufficient for rescuing development of irradiated embryos when its mRNA is injected.
How was it found that neural lineages arise during gastrulation?
The animal cap is a region of the Xenopus blastula and early gastrula stage embryo. It forms the roof of the upper, pigmented half of egg/embryo (the animal hemisphere)
Isolated animal cap largely differentiates into epidermis when isolated prior to gastrulation, but can become neurons when isolated during gastrulation
What is neurulation?
Neurulation - making of the neural plate and neural tube
The notochord induces neuroectodermal differentiation from the ectoderm, which thickens to form the neural plate
Neural plate folds in dorsally to form the neural tube. The two ends will eventually join as the neural tube closes, and the joining part forms the neural crest
Neural tube closure disconnects the neural crest from the epidermis. Neural crest cells eventually forms most of the peripheral nervous system (PNS)
The neural tube will eventually become the spinal cord and the brain (Central nervous system, CNS)
How was it found that neural fate may be a default state of differentiation?
Dissociation of isolated animal cap enhances neural differentiation
Bone morphogenetic protein 4 (BMP4) inhibits neural differentiation –> epidermal cells
BMP4 is member of the bone morphogenetic protein family, which belongs to the transforming growth factor-beta (TGFß) superfamily. This superfamily includes large families of growth and differentiation factors
BMP4 is an important regulator of early embryonic development and is highly conserved evolutionarily
How could BMP signaling be blocked by extracellular antagonists?
BMP ligands bind to the BMP receptors BMPRI and BMPR2 (which forms a receptor complex), and BMPR2 then phosphorylates and activates BMPR1. Phosphorylated BMPR1 subsequently phosphorylates SMAD1, SMAD5 and SMAD8, which associate with SMAD4 and enter the nucleus, where they regulate gene expression.
BMP signal can be blocked by extracellular antagonists, such as noggin, which bind BMP ligands and prevent their association with the BMP receptors.
How do mesodermal organisers drive neural induction?
Mesodermal cells of the involuting marginal zone (IMZ) release BmP antagonist like noggin, chordin, and follistatin that drive neuroectoderm formation
Nervous system patterning of blastula and embryo occurs over which anatomical locations?
Dorsal vs Ventral
Posterior (caudal) vs Anterior (rostral)
How is the general pattern of the nervous system is determined by gradients of secreted factors like EGF, BMPs, Wnt, Shh and RA?
Generally:
1. A growth factor can act either instructively (specifically activate genes required for the development or selectively (promotes he survival of cells that already express specific properties).
2. Timing (when exposed, and to which) is very important
3. The relative amount of different factors is critical
What are the signalling pathways that shape nervous system development?
TGF-β family
Fibroblast Growth Factor (FGF)
Wnt/β-catenin pathway
Hedgehog/Sonic hedgehog pathway
Retinoic acid (RA)
nervous system development
What are the ligand(s), receptors and signal transduction pathways for the TGF-β family?
Ligand:
- Bone morphogenetc proteins (BMPs)
- Nodal
Receptor:
- Type I BMP receptors
- Type II BMP receptors
Signal transduction:
- Ser/Thr kinase receptors, Smads
nervous system development
What are the ligand(s), receptors and signal transduction pathways for Fibroblast Growth Factor (FGF)?
Ligand:
- bFGF
Receptor:
- FGF receptor
Signal transduction:
- Receptor tyrosine kinase
