Axonal Outgrowth and Synapse Formation lecture 1
Lecturer's Background and Expectations:
The lecturer is a developmental biologist by training with a PhD in neuroscience ( years ago).
Transitioned to breast cancer and breast development research but maintained an interest in neuroscience, noting its essential role in mammary tissue specification and development.
French accent is noted; students are encouraged to interrupt for clarifications, rephrasing, or re-explanation.
Lectures are intended to be interactive, with questions from both the lecturer and students, fostering feedback and input.
Lecture Focus: Neural Specification and Development:
The primary goal is to understand how neurons are specified, focusing on the molecular mechanisms that transform an initial cell (often a stem cell) into a defined neural identity through various signals.
These signals lead to the development of different neuron subtypes.
The lectures will also cover how neurons emit axons and dendrites, and how axons are guided to their targets to form connections or synapses.
Three Main Concepts in Neurodevelopment:
Number: The sheer quantity of neurons.
Position: The spatial organization and interaction of neurons.
Shape: The diverse morphologies of neurons.
These three elements work in concert to form the brain.
Impressive Numbers in the Brain:
The human brain contains approximately billion neurons.
Each neuron can form thousands of connections (synapses), leading to an immense number of synapses that contribute to a functional brain.
Programmed Cell Death (Apoptosis) in Neurodevelopment:
A crucial concept: up to of neurons die during development, primarily through apoptosis.
This process is essential for establishing strong and functional synapses by eliminating neurons unable to meet developmental requirements.
This developmental cell death is distinct from the exacerbated cell death mechanisms seen in neurodegenerative diseases like Alzheimer's and Huntington's, although cell death mechanisms are involved in both contexts.
This concept will be revisited in the third of four lectures.
Neurodevelopmental Timeline (Video Summary):
The video illustrates the increase in cell numbers and changes in the central nervous system's shape during the months of human gestation.
By months, there are about million cells, and the nervous system begins to exceed the size of a dime, with the future cerebrum and cerebellum expanding disproportionately.
By months, hundreds of millions of neurons are present, and the brain starts to show familiar convolutions, with initial deep indentations.
By to months, billions of nerve cells (tens of billions) are present, with more cells to be produced to reach the billion adult count.
A remarkable feature is that even in adult life, environmental richness can influence neuron numbers.
This increase in number, coupled with variations in fate, shape, and position, is critical for shaping the brain.
Historical Perspective: Neuron Shape (Ramon y Cajal):
Santiago Ramon y Cajal, over years ago, was a pioneer in studying neuron shapes, drawing many subtypes.
He highlighted the diversity of neuron cell types in the nervous system and their role in underpinning functional aspects of behavior and overall brain functions.
Examples include Purkinje cells and granule cells, each with distinct shapes and proportions that contribute to brain development and final morphology.
Positional Information and Spatial Organization:
Neurons are organized contextually, influencing their interactions with the environment and other neurons.
They integrate signals from their immediate surroundings, neighboring cells, and tissue topology.
Positional information is critical for proper neuronal function.
Brainbow Mouse Model: An example of fate mapping or lineage tracing that labels neurons across almost the entire color spectrum, revealing the immense diversity and packed nature of neurons.
The packed nature implies mechanical constraints and stresses, requiring fine-tuned interactions with their environment and other cells.
Lecture Series Overview:
The course consists of four lectures and one journal club.
Topics: Mechanisms driving neural specification, axon guidance to targets for synapse formation, and fine-tuning of synapse formation.
Goal: Provide general concepts of neural specification and synapse formation.
Resources: Published literature (core papers and primary research paper for journal club), textbook available in the library, and a link to Tom Jessell's lecture for general principles of neural specification.
Students are encouraged to proactively review journal club papers to facilitate lively discussions, as some findings may challenge textbook generalizations, adding complexity to neurodevelopment.
Foundational Concepts Revisited (from previous Neuroscience courses):
Differentiation: The process by which cells become specialized.
Temporal and Spatial Regulation: Neural formation, specification, and synapse formation are precisely regulated across time and space.
Neural Tube Formation and Induction: Begins with neural induction, where specification processes occur along the anterior-posterior axis, segmenting the nervous system and establishing polarity.
Morphogenetic Process: Regulated by various morphogen genes, with developmental structures like the notochord, floor plate, and roof plate of the neural tube playing essential roles by releasing specific molecules.
These molecules act in concert to regionalize the nervous system and define neuron subtypes that build brain networks.
Neural Tube Structure and Inductive Signals:
The neural tube is an epithelial tube organized around a central lumen.
Notochord: A dermal structure specified during gastrulation, located underneath the neural tube, releases Sonic hedgehog (Shh).
Floor Plate: Part of the neural tube, releases Shh and Retinoic Acid (RA), and Chordin (an organizer gene and ligand).
Roof Plate: Part of the neural tube, releases Bone Morphogenetic Protein (BMP), RA, and Noggin (another organizer ligand).
Somites: Also release essential molecules, mainly BMP.
Different gradients of these morphogens are established based on the location of their sources, influencing regional specification.
Inductive Development / Conditional Specification:
Neural specification and development are inductive processes, meaning different structures and cells influence each other based on their interactions and environmental cues.
This induces the differentiation and specification pathways of neural progenitors.
Differential Gene Expression ( Genes):
All body cells contain the same DNA.
Differential gene expression is the fundamental process in development where cells induce specific gene expression networks (either repressed or induced) in response to various signals.
This is the underlying mechanism of inductive development, allowing cells to adopt specific identities despite having the same genetic material.
Morphogens and Their Mechanisms:
Definition: Signaling molecules that inform development and affect gene expression in target cells.
Action: Their effect is concentration-dependent, meaning cells receive and respond to different amounts of morphogen based on their distance from the source.
Receptors: The amount of receptors expressed by target cells also influences their sensitivity and response to morphogens.
Combined, these factors define different neuron subsets.
Four Key Morphogens Discussed: Sonic hedgehog (Shh), Retinoic Acid (RA), Fibroblast Growth Factor (FGF), and Bone Morphogenetic Protein (BMP).
Specific Morphogen Signaling Pathways:
Sonic hedgehog (Shh):
Signaling occurs via Patched receptors.
Absence of Shh: Patched ( and ) inhibits Smoothened, leading to proteolytic maturation of Gli which translocates to the nucleus and acts as a transcriptional repressor.
Presence of Shh: Shh interacts with its co-receptor, releasing Patched's inhibition on Smoothened. This activates Gli, which matures, translocates to the nucleus, and acts as a transcription factor, inducing a transcriptional program for cell specification.
Retinoic Acid (RA):
A lipophilic (cyclic) molecule that can pass through cell membranes to reach its intracellular receptors.
Can have positive or negative effects on transcription factors.
Fibroblast Growth Factor (FGF):
Binds to Receptor Tyrosine Kinases (RTKs), leading to a variety of downstream signaling pathways.
Examples: MAPK signaling for cell proliferation, pathways for cell survival, and cell motility.
The cellular response is context-dependent, balancing these mechanisms according to environmental interactions and other cell types.
Bone Morphogenetic Protein (BMP):
Dual Function:
Inhibits neural tube formation during initial ectoderm specification (antagonized by molecules like Noggin and Chordin to induce the neural plate).
Plays an essential role in neuron specification after neural tube formation.
Signaling Pathway: Part of the TGF-beta signaling pathway, with SMADs as the main downstream effectors.
SMADs form complexes that translocate to the nucleus, activating gene expression programs that define neural progenitor identity.
Cell-to-Cell and Intracellular Signaling:
Reciprocal Activation/Repression: Intracellular transcription factors can activate or repress each other, finely tuning specification.
Cell-Cell Interactions: Interactions between different cells enable the formation of neuron subtypes.
Cell Sorting and Layering: Based on specific receptor expression and pathway activation, cells sort out to form clusters, contributing to essential brain mechanisms like layering.
Notch Signaling Example:
A key pathway for self-renewal of stem cells.
Involves Notch receptors and Delta ligands.
Mechanism: Interaction of Delta on one cell with Notch on a neighboring cell activates Notch, generating an intracellular domain (NICD).
NICD translocates to the nucleus and acts on gene expression.
Feedback Loop: Initially, cells express similar levels of Notch and Delta.
Over time, NICD inhibits Delta expression in its own cell while promoting more Notch receptor expression.
This leads to a divergence: one cell expresses almost no Delta and more Notch, while the other expresses more Delta and almost no Notch.
This feedback process sorts cells, defining distinct cell identities and allowing for the formation of specialized tissues and brain layers.
Concluding Remarks: The introduction provides a simple start to complex concepts, with more specific examples to follow in subsequent lectures.