lecture 3 - Neurodevelopment Flashcards
Four stages in the development of the mammalian nervous system:
- Formation and patterning of neural tube
- Birth and differentiation of neurons and glia
- Growth and guidance of axons
- Formation of synapses
Gastrulation
- transforms a simple, single-layered blastula into a complex, multilayered structure called the gastrula.
- This stage establishes the three primary germ layers—ectoderm, mesoderm, and endoderm—which give rise to all tissues and organs in the body.
Neural tube formation
- The neural plate invaginates, forming the neural groove.
- The fold deepens and eventually separate from the rest of the ectoderm to form the neural tube.
* Caudal region → Spinal cord
* Rostral region → Brain
- Cells at the junction between the closing neural tube and the ectoderm become the neural crest
→ Autonomic nervous system
→ Sensory nervous system
→ Non-neural cell types
Neural induction - What triggers the formation of this neural plate?
- Ectoderm cells synthesize and secrete BMPs (Bone morphogenetic proteins).
→ BMPs suppress the potential for neural differentiation and promote
epidermal differentiation. - The organizer cells secrete BMP antagonists (Chordin, Noggin and Follistatin)
→ Allows ectodermal cells to differentiate into neural tissue
Early during neural development there is rapid but non-uniform cell proliferation.
Formation of 3 brain vesicles:
Proencephalon (Forebrain).
Mesencephalon (Midbrain).
Rhombencephalon (Hindbrain).
Two neural tube flexures occur:
Cervical flexure: between spinal cord and hindbrain.
Cephalic flexure: between midbrain and hindbrain.
A 3rd flexure (pontine flexure) occurs later, and later still the cervical flexure straightens out.
Neural tube regionalisation -
Two brain vesicles divide further, forming a five-vesicles stage:
Proencephalon Telencephalon + Diencephalon
Rhombencephalon Metencephalon + Myelencephalon
This patterning and subdivision of the neural tube is regulated by a variety of secreted signal.
Rostrocaudal patterning of the neural tube
Wnt, FGFs and retinoic acid are signaling factors that initiate the rostrocaudal patterning of the neural tube.
Wnt signaling activity level is low at rostral end and increases progressively in the caudal direction:
The mesoderm that flanks caudal region of the neural plate expresses high levels of Wnt
Endoderm that flanks the rostral region secretes Wnt inhibitors.
Dorsoventral patterning of the neural tube
In the spinal cord, the motor and sensory circuits are anatomically separated: cutaneous sensory information is processed dorsally, while the control of motor output is located ventrally.
Ventral patterning:
Dorsal patterning:
Ventral patterning:
Notochord secrete Sonic hedgehog (Shh) Induces floor plate (specialized glial cells), which start secreting Shh Induces ventral neurons
Shh is a morphogene: Difference in Shh signaling activity direct progenitor cells in different ventral domains to differentiate as motor and interneurons.
Dorsal patterning:
Epidermal ectoderm secrete BMP Induce roof plate (specialized glial cells) differentiation, which, after closure of neural tube, start expressing BMP + Wnt.
Wnt Proliferation of progenitor cells in the dorsal neural tube
BMP Differentiation of neural crest cells, and later, generation of sensory relay neurons
Establishing neuronal types: Motor neuron example
One major class of genes involved in specifying motor neuron subtypes is the Hox gene family:
These homeobox genes encode a family of transcription factors that contain a homeodomain, a major class of transcription factors that regulate developmental processes.
The mammalian genome contains 39 Hox genes, organized in four chromosomal clusters.
The position of an individual Hox gene within its cluster predicts its rostrocaudal domain of expression within the neural tube.
Genes at 3′ positions are expressed in more rostral domains
Genes at more 5′ positions are expressed in progressively more caudal positions
Establishing neuronal types: Motor neuron example
Hox genes are expressed in overlapping domains along the rostrocaudal axis of the developing midbrain, hindbrain, and spinal cord.
Specific Hox genes control the identity of neurons in individual rhombomeres
The identity of motor neurons in the spinal cord is also controlled by the coordinate activity of Hox genes
Motor neuron identity is controlled by the spatial distribution of Hox gene expression.
Local signals determine functional subclasses of neurons
The proliferative zones around the ventricles are the major sites of production of neurons and glia in the CNS.
Proliferation of neural progenitor cells involves symmetric and asymmetric cell divisions:
Neural progenitor divide to produce two neuronal progenitors Increased progenitor cells population
Neural progenitor divide to produce one differentiated daughter and one progenitor cells No amplification of progenitor cells population
Neural progenitor divide to produce two differentiated daughters (neuron and/or glia) Deplete progenitor cells population
Incidence of symmetric and asymmetric cell division, and the fate of cells, are influenced by local environmental factors.
Radial glial cells
the first cell type to appear, their cell bodies located at the ventricular zone and their processes extending to the pial surface
Radial glial cells serve as progenitors that generate neurons and astrocytes, in addition to self-renewal cell division.
They also play a role in neuronal migration, serving as a scaffold to migrating neurons.
Neuronal migration
Neurons and glia become committed at the proliferative zones and need to migrate to their final position:
1. Radial migration:
2. Tangential migration:
3. Free migration:
Radial migration:
Excitatory neurons, originating from the cortical ventricular zone, move along the long process of radial glia cells to reach their destination.
Tangential migration:
Interneurons arise from progenitor cells in the ventricular zone of subcortical structures, most of them in regions of the ventral telencephalon called ganglionic eminences.
Interneurons migrate dorsally to enter the cortex, once they reach a particular antero-posterior position they switch to a radial mode of migration to travel to their final destination.
Free migration:
The PNS derive from neural crest stem cells.
Neural crest cells are transformed from epithelial to mesenchymal cells, causing them to detach from the neural tube and migrate into the periphery.
Neural crest migration does not rely on scaffolding, but on secreted factors, as does its differentiation into its various derivatives.
Growth cone
Neurons need to extend processes, where one will be established as the axon and the others, dendrites.
Once an axon forms, it begins to grow toward its synaptic target guided by extracellular cues.
The growth cone is a key element responsible for axonal growth
Growth cones have 3 main compartments:
Central core: rich in microtubules, mitochondria and other organelles
Filopodia: Long slender extension projecting from the body of the growth cone. Rich in actin, highly motile, used to sense environmental signals
Lamellipodia: Motile structure, which lie between the filopodia and give the cone its ruffled appearance
It is both a sensory structure that receives directional cues from the environment
And a motor structure whose activity drives axon elongation
Several motor powers this, with actin and microtubules playing a key role.
Crossing the midline
Certain axons need to project to the opposite side, to coordinate activity on both side of the body.
Both attractive and repellent molecules guide axons across midline structure:
BMP act as a repellent, directing commissural axons ventrally
Netrin attracts commissural axons
Once the axons reach the floor plate, Slit and Robo act to repel them away, and diminish their sensitivity to netrin to prevent midline recrossing.
Wnt guide axons growth rostrally at the ventral midline.
Major functional regions of the mature CNS
Forebrain:
Mesencephalon (midbrain):
Hindbrain:
Spinal cord
Forebrain
Telencephalon: gives rise to the cortex, hippocampus, amygdaloid nucleus and basal ganglia
Diencephalon: give rise to the thalamus, hypothalamus, and retina.
Mesencephalon (midbrain):
Gives rise to the inferior and superior colliculi and other midbrain structures.
Hindbrain:
Metencephalon: gives rise to the pons and cerebellum
Myelencephalon: gives rise to the medulla.
Two cerebral hemisphere, each divided into four lobes:
Frontal lobe: Higher cognitive processing and motor planning
Parietal lobe: Somatic sensation, location and manipulation of objects (incl. the body image) in the visual space
Temporal lobe: object identity and auditory processing, emotion and memory
Occipital lobe: critical for all aspects of vision
Forebrain:
Telencephalon: gives rise to the cortex, hippocampus, amygdaloid nucleus and basal ganglia
Diencephalon: give rise to the thalamus, hypothalamus, and retina.
Thalamus:
Processes most of the information reaching the cerebral cortex from the rest of the CNS
Hypothalamus
Regulates autonomic, endocrine and visceral functions
Mesencephalon (midbrain):
Gives rise to the inferior and superior colliculi and other midbrain structures.
The midbrain controls many sensory and motor functions, including eye movement and the coordination of visual and auditory reflexes
Hindbrain:
Metencephalon: gives rise to the pons and cerebellum
Cerebellum: Modulates the force and range of movement, and is involved in learning motor skills
Pons: Conveys information about movement from the cerebral hemispheres to the cerebellum
Myelencephalon: gives rise to the medulla.
Medulla oblongata: Includes several centres responsible for vital autonomic functions, such a digestion, breathing and heart rate control
Spinal cord
Receives and processes sensory information from the skin, joints and muscles and control movements of the limbs and trunk.
The cerebral cortex is organised in layers and columns (Generally 6 layers, each with different inputs and outputs):
The cerebral cortex is organised in layers and columns (Generally 6 layers, each with different inputs and outputs):
Layer I (Molecular layer):
Layer II (External granular cell layer):
Layer III (External pyramidal cell layer):
Layer IV (Internal granular cell layer):
Layer V (Internal pyramidal cell layer):
Layer VI (Multiform layer):
Layer I (Molecular layer):
): contains dendrites of cells located in deeper layers and axons which travels through this layer to make connections in other areas of the cortex
Layer II (External granular cell layer):
contains small pyramidal neuron and small spherical neurons
Layer III (External pyramidal cell layer):
contains larger pyramidal neuron
Layer II and III:
Axons of these neurons project locally to other neurons within the same cortical area, as well as to other cortical areas ( intracortical communication)
Layer IV (Internal granular cell layer):
): Contains large number of small spherical neurons. Main recipient of sensory input from thalamus. Is most prominent in primary sensory areas.
Layer V (Internal pyramidal cell layer
): contains pyramidal neurons, larger than those in layer III. They project to other cortical and subcortical areas and are the major output pathway.
Layer VI (Multiform layer):
): Contains neurons heterogenous is shape. It blends into the white mater and carries axons to and from areas of the cortex
