22.1 Neural stem cells, derived from pluripotent stem cells, generate the entire nervous system
Learning goal: Define the capacity of stem cells to generate all cell types in an organism.
Answer: Stem cells—particularly pluripotent stem cells such as embryonic stem (ES) cells and induced pluripotent stem (iPS) cells—have the
capacity to generate all cell types in an organism, including somatic cells (e.g., neurons, muscle cells, skin cells) and germline cells (sperm
and oocytes). This was first demonstrated by nuclear transfer experiments in frogs, where the nucleus of a differentiated somatic cell was inserted
into an enucleated oocyte, producing a full, fertile organism.
These results confirmed that the genetic material in somatic cells remains intact and complete, retaining the ability to give rise to every cell
type, given the right cellular environment and molecular instructions. Pluripotent cells differ from multipotent somatic stem cells, which can
only generate a full range of cells within their specific tissue type (neural stem cells can produce neurons and glia, but not muscle or liver cells).
Learning goal: Describe the molecular and genetic manipulations that are required to make stem cells from somatic cells.
Answer: To generate stem cells from somatic cells, scientists induce pluripotency by introducing specific transcription factors that reprogram the
cell's gene expression profile to resemble that of an embryonic stem cell. Scientists identified a combination of four key transcription factors—
Sox2, Oct4, Klf4, and c-Myc—that, when introduced (commonly via retroviruses) into somatic cells like fibroblasts, can reprogram them into
induced pluripotent stem (iPS) cells.
These iPS cells exhibit the same characteristics as ES cells: infinite self-renewal and the ability to differentiate into all tissue and cell types,
including those of the nervous system and germline. This reprogramming depends on activating genes associated with pluripotency and
restructuring the chromatin architecture to match that of early embryonic cells.
Learning goal: Discuss the properties of neural stem cells and their capacity to make all cell classes of the nervous system.
Answer: Neural stem cells (NSCs) are a specific type of somatic stem cell found in the developing and adult nervous system, or derived in vitro
from ES or iPS cells. NSCs are self-renewing and multipotent, meaning they can divide to produce more stem cells and differentiate into all
three primary neural cell types:
• Neurons
• Astrocytes
• Oligodendrocytes
NSCs express molecular markers such as Sox2, and repress non-neural gene expression through factors like REST/NRSF, which silences neuron-
specific genes in non-neural tissues. Unlike neural progenitor cells, which are lineage-restricted and have limited proliferation, NSCs can
indefinitely self-renew and maintain the potential to generate the full range of neural cell types.
Their fate is regulated by environmental signals and transcription factors that guide them toward specific identities based on location and
developmental stage. NSCs can be experimentally manipulated in vitro to differentiate into neural subtypes resembling those in specific brain
regions.
Learning goal: Assess the uses of stem cells for analysis of nervous system development, disease, and repair.
Answer: Stem cells have several critical applications in studying nervous system development, disease mechanisms, and potential
therapies:
• Developmental Analysis: ES and iPS cells provide models for studying the molecular mechanisms that guide differentiation into neural
tissue. When cultured under specific conditions, these cells mimic embryonic development, revealing how neural identities are specified.
• Disease Modelling: iPS cells derived from patients with neurological disorders can be differentiated into disease-relevant neurons. This
allows researchers to study disease pathology in a controlled environment, especially for conditions where living human brain tissue is
inaccessible (e.g., Alzheimer's, Parkinson’s, Huntington’s).
• Drug Testing and Screening: Disease-specific neural cells derived from iPS cells can be used for high-throughput drug testing to identify
compounds that affect disease progression or symptoms.
• Tissue Repair and Regeneration: Though still experimental, stem cell-based therapies aim to replace lost or damaged neurons in
neurodegenerative diseases and injuries. Examples include generating dopaminergic neurons for Parkinson’s disease or
oligodendrocytes for myelin repair in demyelinating diseases. However, this approach is challenged by the need for precise control over
differentiation, integration into existing neural circuits, and ensuring safety (e.g., avoiding tumor formation).
• Organoids: iPS or ES cells can form brain organoids, 3D structures that contain diverse neural cell types and mimic early brain
development. These are valuable for studying human neurodevelopment and modeling diseases at a structural and cellular level.
1|Page
,22.2 Neural stem cells generate the central and peripheral nervous systems
Learning goal: Explain how gastrulation and neurulation in the embryo establish the entire nervous system.
Answer: Gastrulation is the process where a single sheet of embryonic cells invaginates to form three germ layers: ectoderm, mesoderm, and
endoderm. This process defines the embryo’s anterior–posterior, dorsal–ventral, and medial–lateral axes, which are essential for organizing all
organ systems, including the nervous system.
The notochord, a mesodermal structure, forms at the midline and signals the overlying ectoderm to become neuroectoderm, forming the
neural plate. This plate folds to create the neural tube, from which the central nervous system (CNS) develops. Neural crest cells at the
margins of the neural plate migrate and form much of the peripheral nervous system (PNS). These processes, known as neurulation, are driven
by inductive signals and establish the entire nervous system.
Learning goal: Knows the different germ layers: ectoderm, mesoderm and endoderm.
Answer:
• Ectoderm = outer layer; gives rise to the epidermis and nervous system (via neuroectoderm).
• Mesoderm = middle layer; gives rise to the notochord, somites, muscles, and skeletal system.
• Endoderm = inner layer; forms the gut lining and associated organs.
Learning goal: Can indicate the location of the notochord.
Answer: The notochord is a rod-like structure derived from the mesoderm, located along the midline
of the embryo. It extends from the mid-anterior to posterior and lies beneath the neural plate (future
CNS). It is generated from the primitive pit/streak and defines embryonic axis.
Learning goal: Can describe the formation of the neural tube from the neuroectoderm.
Answer: The neural tube forms from the neuroectoderm, a specialized region of ectoderm above the
notochord. The neural plate thickens and folds at the midline to form the neural groove, which then
fuses to form the neural tube. This tube gives rise to the brain and spinal cord. The roofplate and
floorplate emerge at the dorsal and ventral midlines, respectively, and guide neuronal differentiation.
Learning goal: Can distinguish the anterior from the posterior side of an embryo.
Answer: The anterior–posterior axis is defined during gastrulation. The anterior is toward the head/mouth, and the posterior is toward the
tail/anus. The primitive node forms anteriorly, while the primitive streak extends posteriorly. The notochord runs from anterior to posterior,
aligning with this axis.
Learning goal: Describe the derivation and differentiation of the major
divisions of the peripheral nervous system.
Answer: PNS mainly derives from neural crest cells formed at the lateral
edges of the neural plate. These cells migrate and differentiate into:
• Cranial sensory ganglia (from cranial neural crest),
• Enteric neurons and parasympathetic ganglia (vagal crest),
• Sympathetic ganglia and adrenal medulla cells (trunk crest),
• Additional enteric neurons and sympathetic ganglia (sacral crest).
Cranial placodes, derived from ectoderm, also contribute sensory
receptor neurons for smell, hearing, vision, and facial touch.
2|Page
, Learning goal: Knows which brain areas develop from the
procencephalon, mesencephalon, rhombencephalon, Telencephalon,
Diencephalon, Metencephalon and myelencephalon.
Answer:
Prosencephalon (forebrain):
• Telencephalon → Cerebral cortex, hippocampus, basal ganglia
• Diencephalon → Thalamus, hypothalamus, epithalamus
Mesencephalon (midbrain) → Midbrain structures (e.g., tectum,
tegmentum)
Rhombencephalon (hindbrain):
• Metencephalon → Pons, cerebellum
• Myelencephalon → Medulla oblongata
Learning goal: Can describe the development of the neural crest, roof
and floor plates, somites, sensory neurons, adrenal neurosecretory cells,
autonomic ganglia and melanocytes.
Answer:
• Neural crest: Arises from lateral edges of the neural plate; undergoes epithelial-to-mesenchymal transition and migrates to form PNS
structures, pigment cells, facial cartilage.
• Roof plate: Dorsal midline of neural tube; secretes signals for dorsal neuron identity.
• Floor plate: Ventral midline; provides signals for ventral spinal cord differentiation.
• Somites: Mesodermal structures next to the neural tube; give rise to muscle, vertebrae.
• Sensory neurons: From neural crest; form dorsal root ganglia.
• Adrenal neurosecretory cells: Chromaffin cells of adrenal medulla; from trunk neural crest.
• Autonomic ganglia: Sympathetic and parasympathetic ganglia; neural crest-derived.
• Melanocytes: Pigment-producing cells; from neural crest, migrate into epidermis.
Learning goal: Explain how the cranial placodes generate special sensory organs and peripheral sensory receptor neurons.
Answer: Cranial placodes are ectodermal thickenings in the head that differentiate into:
• Olfactory epithelium (smell),
• Optic vesicle and organ of Corti (hearing),
• Lens and cornea (vision),
• Cranial sensory neurons (trigeminal, geniculate, petrosal, vagal).
These structures interact with neural crest cells to form functional sensory organs and peripheral
sensory neurons that relay stimuli to the CNS.
Learning goal: Describe the derivation and differentiation of the major divisions of the CNS.
Answer: The CNS (brain and spinal cord) develops from the neural tube, which is derived from the neuroectoderm. Region-specific neural
stem cells along the anterior–posterior and dorsal–ventral axes of the neural tube differentiate into:
• Forebrain (cortex, hippocampus, etc.),
• Midbrain,
• Hindbrain (pons, medulla, cerebellum),
• Spinal cord.
Ventral regions (influenced by notochord and floorplate) form motor neurons, while dorsal regions (roof plate and somite signalling) give rise to
sensory neurons and interneurons.
3|Page
Learning goal: Define the capacity of stem cells to generate all cell types in an organism.
Answer: Stem cells—particularly pluripotent stem cells such as embryonic stem (ES) cells and induced pluripotent stem (iPS) cells—have the
capacity to generate all cell types in an organism, including somatic cells (e.g., neurons, muscle cells, skin cells) and germline cells (sperm
and oocytes). This was first demonstrated by nuclear transfer experiments in frogs, where the nucleus of a differentiated somatic cell was inserted
into an enucleated oocyte, producing a full, fertile organism.
These results confirmed that the genetic material in somatic cells remains intact and complete, retaining the ability to give rise to every cell
type, given the right cellular environment and molecular instructions. Pluripotent cells differ from multipotent somatic stem cells, which can
only generate a full range of cells within their specific tissue type (neural stem cells can produce neurons and glia, but not muscle or liver cells).
Learning goal: Describe the molecular and genetic manipulations that are required to make stem cells from somatic cells.
Answer: To generate stem cells from somatic cells, scientists induce pluripotency by introducing specific transcription factors that reprogram the
cell's gene expression profile to resemble that of an embryonic stem cell. Scientists identified a combination of four key transcription factors—
Sox2, Oct4, Klf4, and c-Myc—that, when introduced (commonly via retroviruses) into somatic cells like fibroblasts, can reprogram them into
induced pluripotent stem (iPS) cells.
These iPS cells exhibit the same characteristics as ES cells: infinite self-renewal and the ability to differentiate into all tissue and cell types,
including those of the nervous system and germline. This reprogramming depends on activating genes associated with pluripotency and
restructuring the chromatin architecture to match that of early embryonic cells.
Learning goal: Discuss the properties of neural stem cells and their capacity to make all cell classes of the nervous system.
Answer: Neural stem cells (NSCs) are a specific type of somatic stem cell found in the developing and adult nervous system, or derived in vitro
from ES or iPS cells. NSCs are self-renewing and multipotent, meaning they can divide to produce more stem cells and differentiate into all
three primary neural cell types:
• Neurons
• Astrocytes
• Oligodendrocytes
NSCs express molecular markers such as Sox2, and repress non-neural gene expression through factors like REST/NRSF, which silences neuron-
specific genes in non-neural tissues. Unlike neural progenitor cells, which are lineage-restricted and have limited proliferation, NSCs can
indefinitely self-renew and maintain the potential to generate the full range of neural cell types.
Their fate is regulated by environmental signals and transcription factors that guide them toward specific identities based on location and
developmental stage. NSCs can be experimentally manipulated in vitro to differentiate into neural subtypes resembling those in specific brain
regions.
Learning goal: Assess the uses of stem cells for analysis of nervous system development, disease, and repair.
Answer: Stem cells have several critical applications in studying nervous system development, disease mechanisms, and potential
therapies:
• Developmental Analysis: ES and iPS cells provide models for studying the molecular mechanisms that guide differentiation into neural
tissue. When cultured under specific conditions, these cells mimic embryonic development, revealing how neural identities are specified.
• Disease Modelling: iPS cells derived from patients with neurological disorders can be differentiated into disease-relevant neurons. This
allows researchers to study disease pathology in a controlled environment, especially for conditions where living human brain tissue is
inaccessible (e.g., Alzheimer's, Parkinson’s, Huntington’s).
• Drug Testing and Screening: Disease-specific neural cells derived from iPS cells can be used for high-throughput drug testing to identify
compounds that affect disease progression or symptoms.
• Tissue Repair and Regeneration: Though still experimental, stem cell-based therapies aim to replace lost or damaged neurons in
neurodegenerative diseases and injuries. Examples include generating dopaminergic neurons for Parkinson’s disease or
oligodendrocytes for myelin repair in demyelinating diseases. However, this approach is challenged by the need for precise control over
differentiation, integration into existing neural circuits, and ensuring safety (e.g., avoiding tumor formation).
• Organoids: iPS or ES cells can form brain organoids, 3D structures that contain diverse neural cell types and mimic early brain
development. These are valuable for studying human neurodevelopment and modeling diseases at a structural and cellular level.
1|Page
,22.2 Neural stem cells generate the central and peripheral nervous systems
Learning goal: Explain how gastrulation and neurulation in the embryo establish the entire nervous system.
Answer: Gastrulation is the process where a single sheet of embryonic cells invaginates to form three germ layers: ectoderm, mesoderm, and
endoderm. This process defines the embryo’s anterior–posterior, dorsal–ventral, and medial–lateral axes, which are essential for organizing all
organ systems, including the nervous system.
The notochord, a mesodermal structure, forms at the midline and signals the overlying ectoderm to become neuroectoderm, forming the
neural plate. This plate folds to create the neural tube, from which the central nervous system (CNS) develops. Neural crest cells at the
margins of the neural plate migrate and form much of the peripheral nervous system (PNS). These processes, known as neurulation, are driven
by inductive signals and establish the entire nervous system.
Learning goal: Knows the different germ layers: ectoderm, mesoderm and endoderm.
Answer:
• Ectoderm = outer layer; gives rise to the epidermis and nervous system (via neuroectoderm).
• Mesoderm = middle layer; gives rise to the notochord, somites, muscles, and skeletal system.
• Endoderm = inner layer; forms the gut lining and associated organs.
Learning goal: Can indicate the location of the notochord.
Answer: The notochord is a rod-like structure derived from the mesoderm, located along the midline
of the embryo. It extends from the mid-anterior to posterior and lies beneath the neural plate (future
CNS). It is generated from the primitive pit/streak and defines embryonic axis.
Learning goal: Can describe the formation of the neural tube from the neuroectoderm.
Answer: The neural tube forms from the neuroectoderm, a specialized region of ectoderm above the
notochord. The neural plate thickens and folds at the midline to form the neural groove, which then
fuses to form the neural tube. This tube gives rise to the brain and spinal cord. The roofplate and
floorplate emerge at the dorsal and ventral midlines, respectively, and guide neuronal differentiation.
Learning goal: Can distinguish the anterior from the posterior side of an embryo.
Answer: The anterior–posterior axis is defined during gastrulation. The anterior is toward the head/mouth, and the posterior is toward the
tail/anus. The primitive node forms anteriorly, while the primitive streak extends posteriorly. The notochord runs from anterior to posterior,
aligning with this axis.
Learning goal: Describe the derivation and differentiation of the major
divisions of the peripheral nervous system.
Answer: PNS mainly derives from neural crest cells formed at the lateral
edges of the neural plate. These cells migrate and differentiate into:
• Cranial sensory ganglia (from cranial neural crest),
• Enteric neurons and parasympathetic ganglia (vagal crest),
• Sympathetic ganglia and adrenal medulla cells (trunk crest),
• Additional enteric neurons and sympathetic ganglia (sacral crest).
Cranial placodes, derived from ectoderm, also contribute sensory
receptor neurons for smell, hearing, vision, and facial touch.
2|Page
, Learning goal: Knows which brain areas develop from the
procencephalon, mesencephalon, rhombencephalon, Telencephalon,
Diencephalon, Metencephalon and myelencephalon.
Answer:
Prosencephalon (forebrain):
• Telencephalon → Cerebral cortex, hippocampus, basal ganglia
• Diencephalon → Thalamus, hypothalamus, epithalamus
Mesencephalon (midbrain) → Midbrain structures (e.g., tectum,
tegmentum)
Rhombencephalon (hindbrain):
• Metencephalon → Pons, cerebellum
• Myelencephalon → Medulla oblongata
Learning goal: Can describe the development of the neural crest, roof
and floor plates, somites, sensory neurons, adrenal neurosecretory cells,
autonomic ganglia and melanocytes.
Answer:
• Neural crest: Arises from lateral edges of the neural plate; undergoes epithelial-to-mesenchymal transition and migrates to form PNS
structures, pigment cells, facial cartilage.
• Roof plate: Dorsal midline of neural tube; secretes signals for dorsal neuron identity.
• Floor plate: Ventral midline; provides signals for ventral spinal cord differentiation.
• Somites: Mesodermal structures next to the neural tube; give rise to muscle, vertebrae.
• Sensory neurons: From neural crest; form dorsal root ganglia.
• Adrenal neurosecretory cells: Chromaffin cells of adrenal medulla; from trunk neural crest.
• Autonomic ganglia: Sympathetic and parasympathetic ganglia; neural crest-derived.
• Melanocytes: Pigment-producing cells; from neural crest, migrate into epidermis.
Learning goal: Explain how the cranial placodes generate special sensory organs and peripheral sensory receptor neurons.
Answer: Cranial placodes are ectodermal thickenings in the head that differentiate into:
• Olfactory epithelium (smell),
• Optic vesicle and organ of Corti (hearing),
• Lens and cornea (vision),
• Cranial sensory neurons (trigeminal, geniculate, petrosal, vagal).
These structures interact with neural crest cells to form functional sensory organs and peripheral
sensory neurons that relay stimuli to the CNS.
Learning goal: Describe the derivation and differentiation of the major divisions of the CNS.
Answer: The CNS (brain and spinal cord) develops from the neural tube, which is derived from the neuroectoderm. Region-specific neural
stem cells along the anterior–posterior and dorsal–ventral axes of the neural tube differentiate into:
• Forebrain (cortex, hippocampus, etc.),
• Midbrain,
• Hindbrain (pons, medulla, cerebellum),
• Spinal cord.
Ventral regions (influenced by notochord and floorplate) form motor neurons, while dorsal regions (roof plate and somite signalling) give rise to
sensory neurons and interneurons.
3|Page
