Developmental Neuroscience - Genesis and Migration

Genesis and Migration

Overview

  • Discussion of the development of the neural tube, neural progenitor cells, and the mechanisms behind neurogenesis and migration.

Neural Tube Development

Initial Structure

  • The neural tube in most vertebrates begins as a single layer thick.

  • As neurogenesis progresses, progenitor cells undergo numerous cell divisions, resulting in a significantly thicker neural tube.

Cell Migration in the Neural Tube

  • Progenitor cells extend one process towards the central canal of the neural tube, termed the ventricular surface due to its continuity with the brain's ventricles.

  • The other process extends to the outer surface of the neural tube.

  • This process is characterized by interkinetic nuclear migration, which involves:

    • Constant movement of the nuclei towards the inner (ventricular) surface before mitosis occurs (during G2/M phases).

    • Neurons and glial cells subsequently migrate away from the ventricular surface to differentiate in their respective locations.

Tracking Progeny

Clonal Analysis

  • A retrovirus containing DNA that codes for green fluorescent protein (GFP) is injected into the developing brain to infect proliferating progenitor cells.

  • The progeny of these infected cells continue to express the GFP gene even in adult animals.

  • This method allows for tracking the development of cells from a single progenitor, leading to the identification of these cells as a “clone.”

Cortical Formation

Neuronal Layering

  • Neurons generated on different embryonic days are found in specific cortical layers:

    • Neurons “born” on E13 are located in deep cortical layers.

    • Neurons generated on E15 are found in more superficial cortical layers.

Progenitor Cell Potential

Restriction of Potential

  • The potential of progenitor cells progressively restricts over time.

  • Unipotent progenitor cells are derived from multipotent progenitors.

Control of Neuron and Glial Production

  • Important questions include:

    • What regulates the quantity of neurons and glia produced by progenitor cells?

    • How does a progenitor cell “decide” whether to differentiate into a neuron or a glial cell?

    • What guides the migration of cells from the ventricular zone to their final locations in the brain?

Mitogenic Factors

Mitogens

  • Mitogens stimulate cells to enter the cell cycle. Major examples include:

    • Epidermal Growth Factor (EGF)

    • Fibroblast Growth Factors (FGF)

  • Mitogens promote CycD expression or stabilization, inhibiting negative regulators and promoting the transition to S-phase.

  • Additional signaling molecules that enhance progenitor cell proliferation include:

    • Sonic hedgehog (Shh)

    • Wnt

Stop Signals in Cell Cycle Regulation

Key Proteins

  • The Rb protein is named after retinoblastoma, a childhood tumor; its defects lead to uncontrolled retinal progenitor proliferation.

  • Cyclin-dependent kinase inhibitors (CdkIs):

    • p27kip and p21 are expressed in the nervous system during the final mitotic cycle of a progenitor cell, which leads to its exit from the cell cycle and subsequent differentiation into neurons or glia.

Generation of Neurons and Glia

Developmental Stages

  • Somatic cells can be reprogrammed to become embryonic stem cells (ESCs) or induced pluripotent stem cells (iPSCs) and then further differentiate into neural stem cells (NSC) or neural progenitor cells (NPC).

  • Cells undergo expansion followed by differentiation into:

    • Neurons

    • Astrocytes

    • Oligodendrocytes

Neuroepithelial Cell Division

  • Neuroepithelial cells perform symmetric division for self-renewal, while subsequent asymmetric division leads to the formation of radial glial cells.

  • Radial glial cells can further generate neurons or basal progenitors during the neurogenic phase, and eventually differentiate into astrocytes during the gliogenic phase.

Factors Influencing Neurogenesis

Extrinsic and Intrinsic Factors

Control of Neurogenesis

  • Factors influencing the number of neurons and glia produced include: - Shh, FGF, and other intrinsic signaling pathways.

Multipotency and Progenitor Cells

  • Neural stem cells differentiate into various progenitor cells, including:

    • Neuronal Progenitor Cell

    • Glial Progenitor Cell

  • Key factors such as Bmi1, Notch, Ascl1, TLX, Wnt, and Sox2 are vital for maintaining multipotency.

Notch Signaling Pathway

Role of Notch in Progenitor Maintenance

  • Notch ligands activate Notch receptors in progenitor cells, leading to the expression of Hes genes, necessary for maintaining progenitor states.

  • Blocking the Notch receptor causes premature differentiation of progenitor cells into neurons.

Proneural Genes and Neurogenesis Regulation

  • Proneural genes, such as Ascl1 and Neurog2, regulate neurogenesis through feedback loops involving Notch signaling.

Oligodendrocyte Development

Origin and Migration

  • Both oligodendrocytes and neurons arise from a common stem cell pool in the ventricular layer of the developing neural tube.

Mechanisms of Fate Determination

Oscillatory Patterns in Gene Expression

  • The oscillations of Hes1, which represses its transcription, create a feedback loop facilitating the differentiation process.

  • Time-dependent expression results in the differentiation of some progenitor cells into neurons, while others remain as progenitors leading to development as astrocytes or oligodendrocytes based on their gene expression levels.

  • Cells maintain expressions of Ascl1 and subsequent molecules, leading to specific fates such as neurons or glial cells.

Cerebral Cortex Histogenesis

Overview of Histogenesis

  • Histogenesis is essential for creating architecturally organized brain regions.

Developmental Mechanisms

  • Various factors, including FGF2, FGF8b, IGF, and signaling pathways like Notch and Wnt, regulate the process.

Variations in Neuronal Composition

Regional Functions

  • Neocortex variations lead to specific functions in different cortical regions—differences in neuron type and quantity based on functional areas.

Areas of Interest

  • Studies show regional variations contribute to area-specific microcircuits and information processing within the cerebral cortex.

Cerebellar Cortex Development

Neuron Arrangement and Layering

  • The cerebellar cortex's neurons exhibit a highly organized arrangement, notably with large Purkinje cells forming a single layer.

  • Granule cells are positioned below and feature T-shaped axons.

Migration and Developmental Pathways

  • Granule cell precursors originate from the rhombic lip region adjacent to the IV ventricle, migrating to accumulate in the external granule layer, eventually settling beneath Purkinje cells.

  • The Bergmann glial cells guide these migrating neurons.

Shh Pathway Influence

  • Granule cells are significantly influenced by the Shh pathway, with fluctuations in this pathway leading to increased or decreased granule cell production.

  • Medulloblastoma serves as an example of disrupted granule cell regulation via the Shh pathway.

Molecular Mechanisms in Neuronal Migration

Role of Reelin

  • Reelin, produced by Cajal-Retzius cells, is vital for proper cortical neuron migration. Mutations in relevant genes lead to defects similar to those seen in reeler mice.

  • Hypotheses for Reelin's function:

    1. Acts as a chemoattractant, guiding migrating neuroblasts toward it.

    2. Acts as a stop signal for neuroblasts, facilitating layer formation in the cortex.

Additional Migration Factors

  • Besides Reelin, multiple other molecules (e.g., Astrotactin, Integrins, Neuregulin) have been implicated in the mechanisms governing neuroblast migration throughout the cortex and cerebellum.

Questions for Consideration

Developmental Implications

  • What consequences arise from a lack of polarization in neural development?

  • Is the cerebral cortex a homogeneous structure?