18. Developmental Genetics

Animal Development

• Defined as the process by which a fertilized ovum becomes a mature organism.

• Development involves:

  • Division and growth of the fertilized egg into various cell types, tissues, and organs.

  • Arrangements dictated by the organism's genes, leading to species-specific body plans.

Cell Determination

• Totipotent cell: Capable of developing into any cell type.

• Plasticity: Ability of a cell to change fate based on environment or gene expression.

• Determination: Commitment of a cell to a specific fate.

• Cloning: experiments on animals.

Skeletal Muscle Development

• Key Transcription Factors in Muscle Differentiation:

  • MyoD, Myf-5, Myogenin, MRF4 determine muscle characteristics and differentiation.

Myoblast Fusion to Form Myotubes

• Identification of Skeletal Muscle Fusion Factors:

  • Myomaker:

    • Involved in membrane hemifusion, enabling early fusion intermediate formation.

  • Myomerger:

    • Drives fusion pore formation and completes myoblast fusion.

  • Notably, their interaction is not required for function.

Skeletal Muscle Plasticity Examples

• Plasticity Phenomena:

  • Differentiation into fast or slow muscle fibers, innervation patterns, exercise-induced adaptations, and nerve growth factors.

Peripheral vs. Central Nervous System

• PNS:

  • Consists of the nerves and ganglia outside the brain and spinal cord.

  • Remarkable capacity to regenerate after injury, contrasting the CNS.

  • The PNS connects the CNS to body parts and serves as a relay mechanism.

• CNS:

  • Consists of the brain and spinal cord

  • Integrates information and influences bodily activities.

PNS Injury Response

• Research indicates injury-induced reprogramming in PNS aids regeneration.

• Dorsal Root Ganglia (DRG):

  • Bipolar neuron structure with unique regeneration rates post-injury (~1 mm/day for peripheral branch vs. limited central branch regeneration).

Cloning

• Plants: Cloning from isolated plant cells does not lose original genetic material during development.

• Animals: Dolly the Sheep

  • Cloned in 1996 from a differentiated adult cell and significant as the first mammal cloned from an adult cell.

Human Infant Development Stages

• Pre-embryonic Stage (conception - 19d)

  • Key timings and developments (e.g. first cell division at 30h, zygote in uterine cavity at 4d, etc.).

• Embryonic Stage (4w - 12 w)

  • Formation of the brain, heart, limbs, and sexual differentiation.

• Fetal Stage (16w - 38w)

  • Rapid growth and maturation of organs, with the fetus becoming more recognizable as a human by the end of this period.

Organ and Tissue Origins

• Ectoderm: skin, nervous system, and sensory organs, including the brain and spinal cord.

• Mesoderm: muscles, bones, the circulatory system, and various internal organs such as the kidneys and gonads.

• Endoderm: the lining of the digestive tract, respiratory system, and associated organs like the liver and pancreas.

Pattern Formation in Development

• Defines how ordered spatial arrangements of differentiated cells create tissues and organs.

• Steps to pattern formation:

  • Definition of cells of a region.

  • Establishment of signaling centers that provide positional information.

  • Differentiation of cells within a region in response to additional cues.

• Genes establish concentration gradients of morphogens that act as transcription factors that activate genes during cell development.

Genes Involved:

• Egg-polarity genes:

  • determine body axes, with transcriptions from maternal origins influencing embryonic development.

• Segmentation genes:

  • determines the number and orientation/polarity of the body segments.

• Homeotic genes:

  • determine the identity of individual segments that have been established.

  • encode DNA-binding proteins

  • 2 major clusters in Drosophila:

    • Antennapedia complex: head and anterior thoracic segments

    • Bithorax complex: posterior thoracic and abdominal segments

• Hox genes:

  • Animals: a subset of homeotic genes that are crucial for establishing the anterior-posterior axis.

  • Expressed along the dorsal axis

  • Temporal Colinearity: 3’ expressed before the 5’

  • Spatial Colinearity: 3’ expressed anterior to the 5’

Hox Genes in Humans

• Positioning and expression of Hox genes reflecting limb and organ patterning

• Lead to the formation of various body structures dealing with L/R symmetry.

• Mutations in Hox genes lead to symmetry disorders.

  • Can cause randomization (situs ambiguus) or L/R reversal (situs inversus)

  • Often shown in conjoined twins

• ZIC3 gene mutations are the most common known genetic cause of human laterality defects

Paracrine Signaling Molecules

• Description of paracrine factors, their functions, and major families contributing to cellular signaling.

FGFR

• Fibroblast growth factor receptors (FGFR) are a family of receptor tyrosine kinases that are expressed in developing bone.

• There are 4 FGFR genes

FGFR3 Mutations and Disorders

• FGFR3 restrains chondrocyte proliferation and differentiation

• FGFR3 mutations affecting bone growth and associated phenotypes.

• Overactivation leads to skeletal defects with varying severities corresponding to mutation degrees.