Fundamentals of Neurobiology - Module 3, Lecture 1: Neural Embryology

Cognition and Language Development

  • The development of cognition and language involves complex processes:

    • Starts from a single cell (zygote) and develops into an adult brain.

    • Adult brain has approximately 86 billion neurons and 200 trillion synapses.

    • Key developmental processes include:

      • Neuronal migration.

      • Myelination.

      • Neural circuit formation and maintenance.

      • Synapse pruning.

  • These processes are related to:

    • Consciousness.

    • Addiction.

    • Depression.

    • Sleep/wake cycles.

    • Emotional responses.

Neural Embryology: From Zygote to Brain

  • Zygote (1 cell) develops into a brain with 86 billion neurons and up to 860 billion glia.

  • Key questions:

    • When do these developments occur?

    • Where do they occur?

    • What mechanisms are involved?

    • How do these mechanisms work?

Lecture 1 Overview: Neural Induction and Proliferation

  • Focus:

    • Initiation of nervous system development.

  • Sections:

    • Neural embryology I & II.

    • Neuronal proliferation/diversification.

    • Formation of the peripheral nervous system (PNS).

  • Neural induction: the process by which non-neuron cells become neurons.

Lecture 1.1: Neuroembryology (Gastrula to Neural Tube)

  • Major landmarks:

    • Gastrula.

    • Neural plate.

    • Neural fold.

    • Neural tube.

  • Formation of the neural plate, neural fold, and neural tube.

  • Three major types of neural tube closure defects.

Lecture 1.2: Primary and Secondary Brain Vesicles

  • Three major divisions of primary brain vesicles.

  • Five major divisions of secondary brain vesicles.

  • Correlations between secondary brain vesicles and brain regions.

Lecture 1.3: Neuronal Cell Proliferation and Diversification

  • Symmetrical cell division leads to an increase in neuronal progenitor cells.

  • Asymmetrical cell division leads to an increase in neuronal cell types.

  • Neuroepithelial cells & radial glial cells go through:

    • Neurogenesis.

    • Gliogenesis.

  • Control of neuronal cell diversity along:

    • Dorsal-ventral axes by gradients of dorsalization and ventralization factors.

    • Anterior-posterior axes by gradients of anteriorization and posteriorization factors.

  • Consequences of soluble factor gradient perturbation on neurodevelopment.

Lecture 1.4: Formation of PNS

  • Origin of neural crest cells during neural tube formation.

  • Formation of PNS neurons and glia from neural crest.

  • Neurocristopathy: disorder of neural crest development.

Lecture 1 Glossary

  • Cleavage: Rapid cell division during early embryonic development, producing a cluster of cells of similar size to the original zygote.

  • Blastula: An embryonic stage with a hollow ball of cells, before cell differentiation.

  • Gastrula: An embryonic stage after blastula, marked by cell differentiation into three germ layers:

    • Ectoderm: Forms epithelial tissues and the nervous system.

    • Mesoderm: Develops into muscles, bones, and connective tissues.

    • Endoderm: Gives rise to endothelial linings of organs and glands.

  • Notochord: A rod-shaped structure from the mesoderm that initiates neural plate formation through sonic hedgehog secretion.

  • Neural Plate: A thickened plate of ectoderm above the notochord, which develops into the neural tube.

  • Neural Groove: An intermediate structure formed from the neural plate folding to form the neural tube, regulated by sonic hedgehog and bone morphogenetic proteins.

  • Neural Tube: A hollow tube formed from the infolding and fusion of the neural plate, which develops into the brain and spinal cord.

  • Neural Crest: Ectoderm-derived cells left out during neural tube formation, giving rise to PNS neurons, glia, and neuroendocrine cells.

Lecture 1 Glossary Cont'd:

  • Primary Brain Vesicles: Three initial divisions of the neural tube:

    • Prosencephalon (forebrain).

    • Mesencephalon (midbrain).

    • Rhombencephalon (hindbrain).

  • Secondary Brain Vesicles: Five brain vesicles formed from the primary brain vesicles:

    • Prosencephalon divides into telencephalon (cerebrum) and diencephalon (thalamus and hypothalamus).

    • Mesencephalon remains mesencephalon (midbrain).

    • Rhombencephalon divides into metencephalon (pons and cerebellum) and myelencephalon (medulla).

  • Neural Induction: Process by which an ectoderm-derived cell becomes a neuron.

  • Symmetrical Cell Division: Parent cell gives rise to two identical daughter cells, increasing cell number (proliferation) but not cell diversity.

  • Asymmetrical Cell Division: Parent cell gives rise to one identical daughter cell and one different daughter cell, increasing cell diversity without increasing parent cell number.

  • Neuronal Progenitor: An ectoderm-derived cell fated to become a neuron.

Lecture 1 Glossary Cont'd:

  • Dorsalization: Formation of cell types located at or near the dorsal side of the nervous system.

  • Ventralization: Formation of cell types located at or near the ventral side of the nervous system.

  • Anteriorization: Formation of cell types located at or near the anterior end of the nervous system.

  • Posteriorization: Formation of cell types located at or near the posterior end of the nervous system.

  • Neurocristopathy: Diseases caused by issues in neural crest cell formation, migration, and differentiation.

Time Table of Major Neural Developmental Landmarks

  • Gastrulation: 2nd week.

  • Neural tube formation:

    • Formation: 3rd - 4th week.

    • Hollowing: 4th - 8th week.

  • Neural proliferation: 2nd – 5th month.

  • Neuronal migration: 3rd – 5th month…birth.

  • Glial proliferation: 6th month – 6th month postnatal…adult.

  • Synaptogenesis:

    • Synapse formation: 6th month – 3 years…adult.

    • Synaptic pruning: 1 year – 16 years…adult.

  • Myelination: 6th month postnatal -3 years…30 years.

  • Predominantly before/by birth: neural induction, neural proliferation and migration.

  • Predominantly after birth: Synapse formation and pruning, and myelination.

Neural Embryology: Gastrula to Neural Tube Formation

  • Sequence of developmental events.

  • Regulation of development.

  • Consequences of perturbation.

Learning Objectives:

  • Describe the sequence of neural tube formation.

  • Describe the regulation of neural tube development.

  • Explain how perturbation of neural tube formation result in neurological disorders.

Neural Embryology: From Inception to Gastrulation

  • Zygote undergoes cleavage and mitosis to form an eight-cell blastula.

  • Cell migration and differentiation lead to the formation of the gastrula.

  • Gastrulation:

    • Marks the beginning of cell differentiation and migration.

    • Key step in neural development.

    • Occurs in the 2nd week.

Gastrulation: Formation of Three Germ Layers

  • Ectoderm: Outermost layer.

    • Generates epithelium and nervous tissue.

  • Mesoderm: Middle layer.

    • Generates most of the muscle, blood, and connective tissues.

    • Generates notochord for regulating neural tube development.

  • Endoderm: Innermost layer.

    • Forms endothelial linings and associated glands of the gut, lung, and urogenital tracts.

Neural Embryology: From Gastrula to Neural Tube

  1. Neural plate forms.

  2. Neural groove forms.

  • Ectoderm, mesoderm, and endoderm are present.

  1. Neural tube forms.

  • Signaling molecules involved.

Neural Plate Formation (Day 19)

  • Initiated by Sonic Hedgehog (SHH) from the notochord (derived from mesoderm).

  1. Notochord forms from the mesoderm.

  2. Ectoderm adjacent to the notochord forms the neural plate.

Neural Groove Formation (Day 20)

  • Neural plate folds to form the neural groove and neural folds.

  • SHH from the notochord induces the formation of the floor plate.

  • BMPs from ectoderm flanking the neural plate coordinate the folding process.

Neural Tube Formation (Days 21-28)

  1. Neural folds fuse to form the neural tube.

  2. The tube separates from the overlying ectoderm.

  3. The fully formed neural tube has a roof plate (dorsal) and a floor plate (ventral).

  • BMPs from the overlying ectoderm induce the formation of the roof plate.

  • The roof plate takes over BMP secretion for dorsal morphogenesis of the neural tube.

  • The floor plate takes over SHH secretion for ventral morphogenesis as the notochord dies.

Completion of Neural Tube Formation

  • Neural tube closure starts at the cervical region (day 21).

  • Rostral (anterior) end closes at day 24.

  • Caudal (posterior) end closes at day 28.

Neural Tube Defects (NTDs)

  • Rachischisis: failure of neural tube folding.

  • Anencephaly: failure of anterior end closure.

  • Spina bifida: failure of posterior end closure.

  • NTDs have many genetic and environmental causes.

  • Best prevented by taking folic acid before and during pregnancy.

Defects in Neural Developmental Landmarks

  • Earlier defects are more lethal.

  • Defects can occur at the zygote, gastrula, neural plate, or neural tube stage, leading to death.

Neural Tube Development: Summary

  • Ectoderm forms the neural plate.

  • SHH from the notochord induces the formation of the floor plate.

  • BMPs from flanking ectoderm influence the roof plate.

  • The neural plate forms the neural groove, which then forms the neural tube.

  • The neural tube has a roof plate (dorsal) and a floor plate (ventral).

Neural Embryology Cont'd

  • Primary brain vesicles.

  • Secondary brain vesicles.

  • Correlation of brain vesicles to brain regions.

Learning Objectives:

  1. Describe the formation of primary and secondary brain vesicles from the neural tube.

  2. Predict the development of various brain regions from primary and secondary vesicles.

Overview of Neural Developmental Landmarks

  • Zygote → Gastrula → Neural Plate → Neural Tube → Primary Brain Vesicles → Secondary Brain Vesicles → Brain.

  • Brain has approximately 100 billion nerve cells at birth.

Neural Development: Primary Brain Vesicles

  • The anterior end of the neural tube expands to form three primary brain vesicles:

    • Prosencephalon (forebrain).

    • Mesencephalon (midbrain).

    • Rhombencephalon (hindbrain).

  • The remainder of the neural tube becomes the spinal cord.

Neural Development: Secondary Brain Vesicles

  • Primary brain vesicles further divide into secondary brain vesicles:

    • Prosencephalon → Telencephalon & Diencephalon.

    • Mesencephalon → Mesencephalon.

    • Rhombencephalon → Metencephalon & Myelencephalon.

Neural Development: Fates of Secondary Brain Vesicles

  • Telencephalon → Cerebrum (cortex, hippocampus, basal nuclei).

  • Diencephalon → Thalamus, hypothalamus, and epithalamus.

  • Mesencephalon → Midbrain (PAG, VTA, and Substantia nigra).

  • Metencephalon → Cerebellum and pons.

  • Myelencephalon → Medulla oblongata.

From Neural Tube to Brain: Summary

  • Neural tube gives rise to primary brain vesicles, which then form secondary brain vesicles and ultimately various brain structures.

  • Structures are not drawn to scale.

Neuronal Proliferation and Diversification

  • Mode of neuronal precursor cell proliferation.

  • Asymmetrical vs. symmetrical cell division.

  • Regulation of neuronal precursor cell fate determination:

    • Dorsal-ventral regulation.

    • Anterior-posterior regulation.

Learning Objectives:

  1. Describe the 3 major cellular mechanisms underlying the formation of the CNS.

  2. Explain the mechanisms of neuronal symmetrical and asymmetrical cell division and how each process contributes to the cell number and cell diversity of the CNS.

  3. Predict how opposing gradients of factors influence CNS development.

Molecular Mechanisms Underlying Neural Development

  • Three key processes:

    • Cell division/proliferation.

    • Cell migration.

    • Cell differentiation.

Cell Proliferation in Early Brain

  • Neuronal precursors proliferate in the ventricular zone.

  • Cell body moves up and down between the marginal and ventricular zones during mitosis.

  • Resting phase: ventricular zone.

  • DNA synthesis: marginal zone.

  • Cell division: ventricular zone.

Cell Proliferation and Diversification: Symmetrical vs. Asymmetrical Cell Division

  • Symmetrical Cell Division: 1 parent cell → 2 identical daughter cells.

    • Purpose: increase parent cell population.

  • Asymmetrical Cell Division: 1 parent cell → 1 identical daughter cell & 1 new cell type.

    • Purpose: give rise to a new cell population without affecting parent cell population.

Cell Type Diversification: Neuroepithelial and Radial Glial Cells

  • Neuroepithelial and radial glial cells are major precursor cells that give rise to all neurons and glia in the neural tube.

  • Radial glial cells may produce neurons and glia:

    • Directly via asymmetrical cell division.

    • Indirectly by producing other intermediate precursor cells.

Cell Proliferation and Diversification: Symmetrical and Asymmetrical Division

  • Neuroepithelial cells undergo symmetrical division for progenitor expansion.

  • Radial glial cells undergo symmetrical and asymmetrical divisions.

  • Neurogenic phase: generation of neurons.

  • Gliogenic phase: generation of oligodendrocytes, astrocytes, and ependymal cells.

Generation of Neural Number and Diversity in the Embryonic Brain

  • One neuronal precursor can differentiate into multiple neuronal cell types.

  • Symmetrical cell division increases parent cell population.

  • Asymmetrical cell division increases new cell types and population.

Regulation of Cell Diversification: Neural Tube Patterning

  • Neural tube undergoes dorsal-ventral and anterior-posterior axis patterning.

Dorsal-Ventral Differentiation

  • Example: caudal end of the neural tube (spinal cord).

  • Formation of different cell types is controlled by soluble factor gradients:

    • SHH secreted from the ventral side.

    • BMPs secreted from the dorsal side.

Dorsal-Ventral Differentiation: Rostral End of Neural Tube

  • Formation of the brain is regulated by many factors, including SHH and BMPs.

  • Important factors involved in regulating dorsal-ventral cell fate determination are SHH and BMPs.

Anterior-Posterior Differentiation

  • Regulated by opposing gradients of factors.

  • Anteriorizing factors: Cerberus, Dickopt, Tlc.

  • Posteriorizing factors: Wnt, FGFs, RA.

Neural Patterning Gone Wrong: Holoprosencephaly

  • Abnormal ventral cleavage results in fused brain hemispheres.

  • Caused by a SHH deficiency.

Neural Patterning Gone Wrong: Retinoic Acid Balance

  • Imbalance in retinoic acid (RA) levels affects somatic motor neuron (SMNs) development.

  • Too much RA: increased SMNs.

  • Too little RA: decreased SMNs.

Neural Tube Patterning: Summary of Integrated Signaling

  • Dorsal: BMPs, Ventral: SHH, Anterior: Cerberus, Dickopt, Tlc, Posterior: Wnt, FGFs, RA.

Formation of Peripheral Nervous System

  • Formation of PNS from neural crest.

  • Neurocristopathy.

Learning Objectives:

  1. Describe the formation of the neural crest.

  2. Identify major PNS cells derived from the neural crest.

  3. Propose possible causes of neurocristopathy.

From Ectoderm to Neural Crest

  • Neural crest cells are derived from ectoderm and pinched off during neural tube formation.

  • Neural crest cells migrate to different parts of the body and give rise to a wide variety of cells, including PNS cells.

Formation of PNS Cells

  • Neural crest cells give rise to:

    • Neurons: dorsal root (sensory), cranial sensory, postganglionic sympathetic and parasympathetic.

    • Glia: Schwann cells, satellite cells.

    • Neuroendocrine: adrenal medulla, chromaffin tissue.

    • Melanocytes.

Neurocristopathy

  • A diverse group of disorders arising from abnormal proliferation, migration, and/or differentiation of neural crest cells.

  • Common examples:

    • Hirschsprung disease (lack of enteric ganglia).

    • Congenital central hypoventilation syndrome (CCHS; faulty autonomic respiratory control).

    • Paraganglioma (neuroendocrine tumors).

    • Cleft palate.

Formation of CNS and PNS Cells from Ectoderm

  • Division of ectoderm into surface ectoderm, neural crest and neural tube.

  • Surface ectoderm becomes epidermis.

  • Neural crest becomes:

    • Sympathetic and parasympathetic postganglionic nerves

    • Sensory nerves

    • PNS glia

    • Adrenal medulla

  • Neural tube:

    • Brain

    • Spinal cord

    • Retina

    • Sympathetic and parasympathetic preganglionic nerves