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.

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