Lecture 12: Endoderm Development and More Flashcards
Forms the tubes and organs for digestion and respiration; however, the first major function of the endoderm is to
to induce the formation of mesoderm
Forms the digestive tube that extends the length of the body forms intestines, stomach, esophagus
Respiratory tube forms as an outgrowth of the digestive tube and later develops into lungs
Pharynx forms in the region where digestive and respiratory tubes branch off
Forms the epithelium of several glands e.g. thyroid, thymus etc.
Liver, pancreas and gall bladder develop from ‘budding’ of the digestive tube
Endoderm ________ from the dorsal blastopore lip, followed by convergence and extension (note: similar to mesoderm involution)
What is the involuting endoderm called?
involutes
Endoderm involutes from the dorsal blastopore lip, followed by convergence and extension (note: similar to mesoderm involution)
Involuting endoderm (definitive endoderm)forms a cavity —> the archenteron —> grows and displaces blastocoel
The archenteron serves as the lumen of the digestive tube
What is critical in the development of the endoderm?
Sox17
Dominant-negative mutation of Sox17 (forms repressive instead of active subunits in the protein) ______ endoderm formation in amphibian development
blocks
Mesenchyme cells from lateral plate mesoderm surround the endodermal tubes and form smooth muscle cells around it peristaltic movements to propel food
Presence of specific transcription factors etc. in different regions of the tube allow for regional specification of the endodermal tube
Reciprocal interactions between endoderm and lateral plate mesoderm
Blockage of Wnt signalling in the anterior region
Barx1 transcription factor activates production of sFRPs (secreted frizzled related proteins) Wnt antagonists
Development of liver, pancreas & gallbladder
Liver, pancreas and gallbladder develop from digestive tube ‘buds’ which proliferate and form branches
Dependent on a number of signalling molecules that control the various cell lineages
E.g. pancreas develops from a dorsal and a ventral bud which then grow towards each other and fuse
What are one of the last mammalian organs to fully differentiate?
Lungs are one of the last mammalian organs to fully differentiate
Derivative of digestive tube (laryngotracheal groove —> forms lung buds which then form paired lungs and bronchi)
Differentiation is partly dependent on surrounding mesenchyme (Wnt, Sox2 signalling)
Development of Lungs and Birth
Birth occurs soon after lung development in mammals
Embryonic lung may send the signal to the mother for delivery!
Birth occurs soon after lung development in mammals
Embryonic lung may send the signal to the mother for delivery!
Post-embryonic growth
Developmental changes happen throughout life
Metamorphosis e.g. butterflies, frogs
Regeneration e.g. - Blood and epidermal cells - Digestive tract epithelium - Limb, tail regeneration in some species (geckos)
Life of a frog – Metamorphosis
Metamorphosis is initiated by different hormones and is dependent on the environment. During metamorphosis:
Changes are initiated by hormones. Which ones?
Limbs develop
Tail recedes
Cartilage in the skull is replaced by bone
Tadpole teeth disappear and the mouth / jaw develop
Intestines become shorter
Gills regress and lungs enlarge
Changes initiated by hormones – thyroxine (T4) and tri-iodothyronine (T3)
Hormonal control of metamorphosis
T3 and T4 are key metabolic regulators –> concentration is tightly regulated
Thyroxine (T4) is a prohormone (precursor of a hormone) and is relatively inactive
Type II deiodinase converts T4 to T3 –> active form
Once inside the cell, T3 binds to thyroid hormone receptors (TRs) in the nucleus –> activates gene expression
Type III deiodinase then converts T3 to inactive di-iodothyronine (T2)
Hormonal control of metamorphosis
Low thyroid hormone levels –> no ligand for TRα –> transcription repression through corepressors
Once TRα binds thyroxine —> activation of transcription of T3-sensitive genes through transcription activators
e.g. TRβ is expressed –> feedback loop
Hormonal control of metamorphosis
Low thyroid hormone levels –> no ligand for TRα –> transcription repression through corepressors
Once TRα binds thyroxine —> activation of transcription of T3-sensitive genes through transcription activators
e.g. TRβ is expressed –> feedback loop
Metamorphosis in frogs
Hormones travel to different organs via blood
Tadpole organs can respond to the hormonal signal in four major ways:
Metamorphosis in frogs
Growth of new structures (e.g. hind limbs)
Cell death in existing structures (e.g. tail)
Remodeling of existing structures (e.g. intestines)
Biochemical respecification (e.g. liver enzymes)
Metamorphosis – Growth
T3 induces certain adult specific organs to form e.g. limbs of adult frog, eyelids, nictitating membrane
T3 also induces the proliferation and differentiation of new neurons —> send axons to newly developed structures
Eyes migrate dorsally and rostrally from a lateral position —> gives binocular vision – (A) and (B)
Neuronal projections change accordingly – (C) and (D)
Metamorphosis – Cell death
T3 induces degeneration of the tadpole tail and gills
Initial degeneration is through programmed cell death (apoptosis)
Later degeneration is carried out through other means e.g. by macrophages
Tadpole RBCs are differently shaped than adult digested by macrophages in liver and spleen after adult RBCs are made (Hb switching)
Metamorphosis – Remodeling
Longer intestines are remodelled into smaller ones using existing cells that DEDIFFERENTIATE to become intestinal stem cells
Most of the nervous system gets remodelled e.g. to control different set of muscles in the jaw
Shape of the skull is changed and cartilage is replaced by bone (e.g. white arrowheads)
Some other cartilage structures are remodelled (black arrowheads and arrows)
Metamorphosis – Respecification
T3 induces expression of a new set of genes in existing cells –> new protein products
Tadpoles excrete ammonia while adult frogs excrete urea (requires less water) –> urea cycle enzymes are expressed in the liver –> synthesize urea from ammonia (NH3) and CO2
Metamorphosis – Regional specificity
Transplant experiments using tail and eye have shown that the regional specification is retained in the tissue
The way the tissue responds to thyroid hormone levels is inherent in the tissue
E.g. tail regresses / degenerates even when transplanted into the trunk while the eye cup does not – even when planted in the tail
Regeneration
Reactivation of development in post-embryonic stage to restore missing or damaged tissue
Regeneration
Four different models:
Stem cell-mediated regeneration: stem cells allow the organism to regrow certain organs or tissues e.g. blood cells from hematopoietic stem cells in bone marrow
Morphallaxis: Repatterning of existing tissues (aka transdifferntiation) and little new growth e.g. in hydra
Epimorphosis: Adult structures undergo dedifferentiation to form an undifferentiated cell mass (blastema) that then re-differentiates to specific cells/tissues e.g. frog intestines, limbs
Compensatory regeneration: Differentiated cells divide without losing their differentiation i.e. new cells come from existing cells e.g. mammalian liver cells
Regeneration in flatworm —>
stem cell-mediated (pluripotent), dependent on morphogen gradients
Regeneration in flatworm
E.g. Wnt inhibits the anteriorly expressed head inducer called Erk and Notum (present in anterior head forming regions) acts as an antagonist for Wnt
E.g. Wnt inhibits the anteriorly expressed head inducer called Erk and Notum (present in anterior head forming regions) acts as an antagonist for Wnt
Regeneration in Salamander
Limb regeneration in Salamander is epimorphic —> new limb generated from remaining limb cells
Only the amputated structures grow back e.g. cut at wrist —>only grows new wrist and foot
Cells undergo dedifferentiation to form a REGENERATION BLASTEMA which then re-differentiates
Medical Aspects of Development
With the number of processes, cells and tissues involved, there is a high potential for something to go wrong
Normally there are backups and redundancies that prevent abnormal development
Three major mechanisms that can cause developmental abnormalities:
Genetic mechanisms e.g. mutations, chromosome breaks, changes in the number of chromosomes
Environmental mechanisms – Agents from outside the body e.g. chemicals
Random events (chance)
Genetic errors in development
Genetics based syndromes are generally caused by:
Addition or removal of several genes e.g. aneuploidy – presence of an abnormal number of chromosomes e.g. in Down Syndrome, individuals have an extra copy of chromosome 21 (trisomy 21) cognitive deficiencies, GI and cardiac defects
Genetics based syndromes are generally caused by:
Pleiotropy – one or a pair of genes producing multiple effects
- Mosaic pleiotropy: A gene is critical in different tissues / parts of the body but it is independently expressed in those tissues
- —-> KIT gene is critical in stem cells for blood, pigment and germ cells. Defect causes anemia, albinism and sterility.
Relational pleiotropy: A critical gene is expressed in one tissue but another product from the initial tissue is necessary for normal development in a secondary tissue
—–> MITF gene expression in pigmented retina prevents full differentiation causes malformation of the eye (microphthalmia – small eye)
Environmental mechanisms
Timing of exposure to environmental agents that cause birth defects (teratogens) is important
environmental agents that cause birth defects = teratogens
Thalidomide as a teratogen
Previously used for sedation, nausea, morning sickness
Caused major birth defects - especially in limb development —> shortening or absence of limbs
Kefauver-Harris Drug Amendments Act (1962) required the that manufacturers prove the drugs are both safe and effective before they are approved
Alcohol as a teratogen
Most devastating teratogen based on frequency of its effects and prevalence in society
Fetal alcohol syndrome (FAS) – Condition in which babies born to alcoholic mothers have a small head, specific facial features and a smaller brain
Alcohol is thought to cause defects in neural crest cells
Can cause cell death by generating superoxide radicals
Endocrine disruptors
Can interfere with hormone function is various ways:
Mimic the effect of a natural hormone
e.g. diethylstillbestrol (DES) —> binds to estrogen receptor and mimics estradiol —> very active hormone in building female reproductive tract
Act as antagonists and inhibit hormone-receptor interaction or block synthesis of a hormone
e.g. DDE a product of an insecticide DDT, acts as an anti-testosterone by binding to androgen receptor —-> prevents normal testosterone function
Effect the synthesis, elimination or transportation of a hormone in the body
e.g. an herbicide atrazine elevates the synthesis of estrogen and can convert testes into ovaries in frogs
Some disruptors can ‘prime’ the organism to be more sensitive to hormones later in life
e.g. bisphenol A exposure during fetal development enhances breast tissue response to steroid hormones later in life
Diethylstillbestrol (DES)
E.g. misregulation of Mullerian duct morphogenesis by DES
DES - Diethylstilbestrol is a synthetic estrogen first synthesized in 1938
Was thought to easy pregnancy and prevent miscarriages but it is now classified as an endocrine disruptor
Causes a rare reproductive tract tumor (clear-cell adenocarcinoma) in girls and women who had been exposed to this drug in utero (DES daughter)
Bisphenol A (BPA)
BPA is one of the top 50 chemicals used in the world —> used in plastic production e.g. bottles, toys etc.
Increases cancer susceptibility by making breast tissue more sensitive to estrogens
Causes meiotic defects in maturing mouse oocytes e.g. (A) shows normal chromosome alignment during first meiotic metaphase (B) BPA exposure causes chromosomes to align randomly —> can cause aneuploidy
Cancer as a development disease
Carcinogenesis can be viewed as aberrations of processes that underlie differentiation and morphogenesis
Cancer as a development disease
MicroRNAs are being tested as a possible means of differentiation therapy –
treatment that uses various molecules (e.g. transcription factors, miRNA) to revert the cancer cells to differentiation instead of proliferation
Using stem cells to implement cell-based therapies for various disorders
Stem cell therapy
Stem cell therapy
Model of curing a ‘human disease’ in mouse
Transgenic mouse with human alleles for sickle cell anemia (HbS)
Fibroblast are taken from a tail clip and infected with viruses containing factors known to induce pluripotency
Induced pluripotent stem cells (iPS) are given the DNA containing WT allele (HbA)
