Embryonic Growth & Development

Processes Necessary for Growth

• Hyperplasia (cell proliferation) — more cells via DNA replication + cell division
• Hypertrophy (cell growth) — larger cells via transcription → translation → protein
• Protein degradation — removes improperly made, damaged, or unneeded proteins
• Cell differentiation — cells acquire specialized structure and function
• Apoptosis (programmed cell death) — tissue remodeling and turnover

The Cell Cycle

All DNA condenses during M phase — no transcription occurs. RNA for mitosis must be made in G2.

Regulation: Growth Factor Signaling

Growth factors are secreted locally (paracrine) and activate two key intracellular pathways:

Protein Degradation

Ubiquitin-Proteasome Pathway: Degrades 80–90% of intracellular proteins. E1/E2 enzymes activate ubiquitin; E3 ligases provide target specificity. Necessary for cyclin degradation during cell cycle.

Intracellular degradation requires ATP. Extracellular degradation (matrix proteases, digestive proteases) does not.

Apoptosis

Triggered by death ligands, growth factor withdrawal, DNA damage, or mitochondrial dysfunction.

• Intrinsic pathway: activated within cell (DNA damage, cell stress)
• Extrinsic pathway: activated by external death receptor signal

Both pathways activate caspases that disrupt DNA, organelles, and cytoskeleton.

Genetic Variation & Epigenetics

• SNPs (coding: altered protein; non-coding: altered expression)
• DNA copy number variation, RNA splicing, miRNA
• Epigenetic modifications (methylation, acetylation, phosphorylation, ubiquitination of DNA/histones) — stable across cell cycles, may be heritable, major source of differences between tissues
• Different epigenetic marks → different receptors/signaling molecules → different response to same signal

Stem Cells & Potency

Mechanism

Differentiation is irreversible — daughter cells inherit new characteristics. Driven by accumulating epigenetic changes:

• Polycomb group proteins repress genes during development (silencing)
• Trithorax group proteins maintain gene expression
• Progressive silencing of some genes, activation of others → narrowing of cell fate

Germ Layer Lineages

Blastocyst → epiblast → 3 primary germ layers:

Epithelial vs Mesenchymal Cells

Interconversion occurs: EMT (epithelial → mesenchymal) and MET (mesenchymal → epithelial).

Regulators of Differentiation

• Epigenetic state — developmental history limits future potential
• Cell adhesion — neighborhood of surrounding cells & extracellular matrix
• Growth factor signaling — secreted by neighboring cells; varying concentrations activate different transcription pathways

Maternal to Zygotic Transition

• Maternal mRNAs packaged in the oocyte are used after fertilization but gradually depleted over the first week
• Zygotic genome activates — genes expressed early play key roles in embryonic organization and cell-fate determination
• DNA methylation (epigenetic marks) is massively reduced in early embryos — both paternal (active demethylation) and maternal (passive loss)
• New tissue-specific DNA marks acquired as cells differentiate → loss of totipotency

Gastrulation & Body Axes

Interaction between ectoderm and endoderm forms mesoderm. The primitive streak establishes all 3 body axes (anterior/posterior, dorsal/ventral, left/right). Regulated by growth factors FGF and TGF-β.

Gastrulation involves movements of cell sheets: invagination, ingression, involution, epiboly, intercalation, convergent extension.

Neurulation & Somite Formation

• Neural tube: formed by folding ectoderm → early brain and spinal cord
• Neural crest cells: migrate to become peripheral nervous system, adrenal medulla, melanocytes
• Somites: segmented blocks of paraxial mesoderm along both sides of neural tube. Form sequentially head → tail. Give rise to vertebrae, cartilage, bone, muscle, tendons.
• Failure of neural tube closure → anencephaly (cranial) or spina bifida (caudal). Associated with folic acid deficiency or vitamin A overdose.

Hox Genes & Body Segmentation

• Large family of homeobox-containing transcription factors — conserved from Drosophila to mammals
• 13 paralogous groups on 4 chromosomes (Hox A, B, C, D)
• Expressed along anterior/posterior axis in same order as 3'→5' position on the chromosome
• FGF (from mesoderm) → more posterior Hox expression
• Retinoic acid (from somites) → antagonizes FGF, increasing anterior Hox expression
• Different combinations specify segment identity (head, thorax, abdomen). Hox deletion deletes the corresponding structure.

Regulation Timeline

Limb Bud Development

• Limb buds form after neural tube closes — mesoderm covered by ectoderm
• Proximal structures form first (nearest body), distal last
• Requires interaction between ectodermal FGF8 and mesodermal FGF10
• AER (Apical Ectodermal Ridge) — transplant forms additional limb
• ZPA (Zone of Polarizing Activity) — transplant forms extra set of digits

Endochondral Ossification

Mesenchymal cells condense into cartilage templates → cartilage is progressively replaced by bone. Primary bone forms in the fetus, secondary bone forms postnatally. Long bone growth continues at growth plates until puberty (estrogen causes plate closure).

Hox Genes in Limb & Positional Identity

• Hox proteins regulate transcription of genes encoding growth factors (FGF), cell adhesion, cell cycle, cell migration
• Sensitive to Wnt, FGFs, Pax, T-box signals
• 3' Hox genes → anterior identity; 5' Hox genes → posterior identity
• Hox deletion removes the structure; reduction in expression duration truncates structure (e.g. Basset vs Greyhound leg length)
• Species differences in structures come from differences in timing/level of Hox expression

Related Homeobox Gene Families

Skeletal Muscle Overview

• Largest body component (~1/3 of total body mass), largest cells (100 µm × cm)
• Multinucleated myofibers formed from fusion of mono-nucleated myoblasts
• Myofiber number is fixed near birth — postnatal growth is by hypertrophy (100× increase in fiber volume)
• Two embryonic origins: (1) somite lateral region → limb/abdominal muscle (migratory), (2) somite medial region → back muscle (non-migratory)

Fiber Formation: Two Waves

Fiber type pattern (speed/power in adult) is established during fetal development.

Satellite Cells (Muscle Stem Cells)

All postnatal DNA added to fibers comes from satellite cell fusion. Asymmetric division: one daughter fuses with the fiber, one remains as precursor to maintain stem cell pool. Needed for fiber hypertrophy — more DNA required to support protein synthesis in large fibers.

Growth Regulators

Critical Periods