Ordered Notes on Early Development
I. Introduction and Scope
• The discussion focuses on early development and the early development of the
central nervous system (CNS).
• Development is a phenomenally large field, so the lecture provides "snapshots" to
give a flavor of the process and highlight rules about parameters to look for in any
developmental process.
• Students can contact the instructor via email or ask questions during the session using
the chat or microphone.
II. Developmental Phases and Comparison Across Species
A. Phases of Mammalian Development (Humans and Mouse)
1. Pre-implantation Phase: Occurs before the embryo implants into the uterine wall,
lasting a few days. It involves fertilization, rapid cell division (one cell to two, then
four), and the development of the early embryo enclosed by the zona pellucida (a
hardish flexible shell). The embryo must orchestrate an escape from the zona
pellucida.
2. Gastrulation and Early Organogenesis: A critically important phase lasting about 2
to 8 weeks. This is when all organs begin the process of development.
3. Organogenesis (Long Period): Further development of organs, as most organs do
not complete their development in the early stage.
4. Fetal Growth and Development: The embryo basically gets bigger, though some
organogenesis still takes place, and development continues even after birth.
B. Cross-Species Relevance
• Source of Knowledge: Most of what is known about human development is derived
from the study of other animal species (e.g., mouse, chick, fruit flies, worms,
zebrafish, Xenopus the frog, sea urchins).
• Similarities: Despite differences (e.g., mouse vs. chick), many developmental
features are similar (e.g., starting small, prominent head, CNS development, spinal
cord, limbs, segmentation, eyes, eye sockets, ears, fingers, toes, and a tail, which
humans eventually lose, ending up with a coccyx).
• Value of Models: Animal models are valuable because they can yield lots of
embryos, development often occurs outside the body (e.g., chick), embryos can be
transparent (zebrafish, Xenopus), and development is rapid.
• Homologous Genes: The evolutionary connection is shown by homologous genes
and proteins across species. For example, the function of a knocked-out mouse gene
(engrailed one), which normally ensures cerebellum development, can be restored by
replacing it with the engrailed gene from the fruit fly (Drosophila), despite 500
million years of separation.
III. Essential Cellular and Molecular Mechanisms
A. Four Essential Cellular Processes
These processes occur in all multicellular organisms and underpin anatomical changes:
1. Cell Proliferation: The increase in cell number, moving from one cell to an estimated
37 trillion cells in the adult body.
2. Cell Specialization (Differentiation): The process by which cells adopt specific
fates. One cell can form about 220 different adult cell types, plus subtypes made
temporarily during development.
3. Cell Interaction: Interactions can be physical or through signals sent between cells.
Every cell in the body is bombarded with information (from nearby sources,
hormones, metabolites) that it must process and respond to.
4. Cell Movement: A significant amount of cell movement takes place during embryo
development.
B. Molecular Control
• Genes and Proteins: The human genome has about 20,000 genes, which create
proteins used in various ways, including as signaling molecules.
• Signaling Types:
o Autocrine: Signaling molecules produced by a cell act back on the same cell.
o Paracrine: Signals sent from one cell to a different, nearby cell that responds
(includes morphagens).
o Endocrine: Hormones.
• Gene Classes: Common genes and protein classes required for multicellular animals
include transmembrane proteins (for adhesion, signaling, ion transport) and DNA
binding proteins (like the basic helix family), which are overrepresented in
multicellular species.
IV. Human Pre-implantation Development
• Process: An oocyte is fertilized by sperm, travels down the fallopian tube, and rapidly
divides (1, 2, 4 cells).
• Genome Switch: At the 4-cell stage, the embryo’s own genome switches on
(previously relying on stored messenger RNA). This is a critical point where
development can falter.
• Compaction (Morula): At the 8-cell stage, cells are loosely joined (totipotent). They
then compact, tightly joining to form a morula (resembling a bunch of berries).
• Blastocyst (First Differentiation): Compaction establishes two different
environments and lineages:
1. Trophoectoderm (Outer Cells): About 120 cells that form the placenta
(extraembryonic tissue).
2. Inner Cell Mass (ICM): About 20 cells that are pluripotent (can form all cell
types of the embryo and other extraembryonic tissue, but not the
trophoectoderm).
o The remaining space is the blastocoel cavity, hence the structure is called a
blastocyst.
• Implantation: Around day 6 or 7, the blastocyst escapes the zona pellucida and
attaches to and implants into the uterine wall.
• Twinning: The splitting of the embryo can occur very early (before compaction) or
later. The later the split, the more likely the resulting twins are to be conjoined.
V. Gastrulation and Germ Layers
• Definition: Gastrulation is the formation of the three primary germ layers,
transforming pluripotent ICM cells into multi-potent cells. It is considered a crucial
time in life.
• Primitive Streak: A specialized structure (containing a streak and a node) forms.
• Mechanism: Cells move (cell movement) into and through the primitive streak,
coming out underneath as two of the three germ layers.
o Endoderm (Endo = Inside): Cells that pass through the streak become
endoderm, forming the linings of the gastrointestinal tract, lungs, liver, and
pancreas.
o Mesoderm (Meso = Middle): Cells that pass through the streak become
mesoderm, forming bone, muscle, blood, cartilage, and connective tissue.
o Ectoderm (Ecto = Outside): Cells that do not go through the streak remain
on the outside, forming the surface ectoderm (skin, cornea) and the central and
peripheral nervous system.
• This process involves all four cellular processes: proliferation, differentiation,
communication, and movement.
VI. Organizers and Morphogens
A. Organizers
• Definition: Critically important centers (like streaks and nodes) in a growing embryo
that promote further development.
• Spemann and Mangold (1924): Pioneering experiments showed that a small piece of
tissue called the organizer (from the dorsal lip of the blastopore of one frog embryo)
transplanted to another embryo could control neighboring cells and direct the
formation of an entire secondary body axis, resulting in conjoined twins.
B. Morphogens
• Function: Morphogens are critical inductive signals released from cells (often by
organizers) that contain information; receiving cells process this information and
respond accordingly.
• Mechanism: A cellular response requires both the morphogen (ligand) and a receptor
(on the cell surface or inside the cell).
• Gradients: Morphogens form gradients by diffusing away from the inducing cells.
Close to the source, concentration is high; further away, it is low. These are short-
range effects (up to a millimeter).
o Cells respond differently based on the concentration they observe (e.g., high
concentration instructs differentiation into cell type C; low concentration
means the cell remains cell type A).
o Complexity can be generated quickly, as just two morphagens can potentially
create five different cell types.
• Regulation by Inhibitors: Extracellular inhibitors (e.g., Argos, Chordin, Noggin) can
bind to a morphogen, making it inactive and preventing it from binding to its receptor,
thereby modifying the resulting gradient of activity.
• Examples:
o Sonic Hedgehog (Shh): Creates a gradient important for limb development.
In the chick wing bud, high Shh concentration instructs digit four formation,
middle concentration instructs digit three, and low concentration instructs digit
two.
o Combined Action: Shh and FGF10 work together through competing
gradients to stimulate and inhibit one another, generating repeated branching
structures seen in lung morphogenesis.
VII. Central Nervous System (CNS) Development (Neurulation)
• The Notochord: An organizing center (formed from mesoderm cells passing through
the primitive node) that is built for a specific purpose at the appropriate time and
place, and then disappears.
• Neural Induction: The notochord, located in the mesoderm beneath the ectoderm,
sends signals (morphagens) upwards to the overlying ectoderm.
• Neural Plate Formation: The overlying ectoderm receiving these instructions
differentiates into neural plate (neuroectoderm)—the first morphological sign of the
nervous system (around day 18-20). This plate develops a groove.
o The anterior end of the plate is already specified as the forebrain, midbrain,
and hindbrain, while the posterior end forms the spinal cord.
• Neurulation: The neural plate rolls up (like a zippering motion) to form the neural
tube. This tube pinches off and sits just below the surface ectoderm (future skin
layer).
• Closure: The neural tube has open ends called neuropores:
o The cranial neuropore closes around day 24.
o The caudal neuropore closes around day 25.
• Protection: Somites (developing mesoderm tissue) differentiate to form the vertebrae
(bone) that surround and protect the developing neural tube.
VIII. Developmental Defects and Further Neuronal Development
• Neural Tube Defects: Failure of the neural tube to properly close:
o Spina Bifida: Involves defects in the spinal cord and/or surrounding
vertebrae. Spina bifida occulta is a mild form where a vertebral arch fails to
fuse, often without nervous system pathology.
o Anencephaly: Severe defect where the neural plate fails to roll up, preventing
brain development, leading to stillborn babies.
• Folate: About 60% of neural tube defects are associated with folate deficiency.
Folate levels are critical before pregnancy, as neurulation occurs very early.
• Neuronal Pathfinding: After initial CNS formation, neuronal precursor cells send
out long extensions called neurites (future axons or dendrites).
o Growth Cones: Located at the tips of elongating axons, these structures guide
the cells. They crawl independently, probing the environment by extending
and retracting thin processes called filopodia, often taking circuitous paths to
find appropriate target cells to establish synaptic connections.
IX. Master Genes
• Definition: Very powerful regulatory genes (molecular nodes) that drive specific
developmental events by setting up complex gene circuits.
• Example 1: Eye Development: In the fruit fly, the master gene eyeless (Ey) regulates
a network of genes promoting eye development. If Ey is expressed in a region
destined to become a leg, an eye structure will develop on the leg.
• Example 2: Muscle Development: Forcing chick skin fibroblasts (which are non-
muscle cells) to express the master gene MyoD causes them to turn into highly
elongated, multi-nucleated muscle cells.
Analogy for Morphogen Gradients:
The action of a morphogen gradient is similar to pouring a few drops of strong perfume into a
large room. The person sitting immediately next to the perfume bottle receives a very high
concentration (triggering a strong response, like becoming a specialized cell type C). People
further across the room receive a low concentration (triggering a different response, like
becoming specialized cell type B), while people sitting near the edges might smell nothing at
all, despite being ready to receive the signal (remaining cell type A). The concentration
gradient dictates the fate of the receiving cells.