Lecture 12: Endoderm Development and More

Question 1

Forms the tubes and organs for digestion and respiration; however, the first major function of the endoderm is to

Answer 1

to induce the formation of mesoderm

Question 2

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.

Answer 2

Liver, pancreas and gall bladder develop from ‘budding’ of the digestive tube

Question 3

Endoderm ________ from the dorsal blastopore lip, followed by convergence and extension (note: similar to mesoderm involution)

What is the involuting endoderm called?

Answer 3

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

Question 4

What is critical in the development of the endoderm?

Answer 4

Sox17

Question 5

Dominant-negative mutation of Sox17 (forms repressive instead of active subunits in the protein) ______ endoderm formation in amphibian development

Answer 5

blocks

Question 6

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

Answer 6

Reciprocal interactions between endoderm and lateral plate mesoderm

Question 7

Blockage of Wnt signalling in the anterior region

Answer 7

Barx1 transcription factor activates production of sFRPs (secreted frizzled related proteins) Wnt antagonists

Question 8

Development of liver, pancreas & gallbladder

Answer 8

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

Question 9

What are one of the last mammalian organs to fully differentiate?

Answer 9

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)

Question 10

Development of Lungs and Birth

Birth occurs soon after lung development in mammals

Embryonic lung may send the signal to the mother for delivery!

Answer 10

Birth occurs soon after lung development in mammals

Embryonic lung may send the signal to the mother for delivery!

Question 11

Post-embryonic growth

Answer 11

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)

Question 12

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?

Answer 12

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)

Question 13

Hormonal control of metamorphosis

T3 and T4 are key metabolic regulators –> concentration is tightly regulated

Answer 13

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)

Question 14

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

Answer 14

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

Question 15

Metamorphosis in frogs

Hormones travel to different organs via blood

Tadpole organs can respond to the hormonal signal in four major ways:

Answer 15

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)

Question 16

Metamorphosis – Growth

Answer 16

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)

Question 17

Metamorphosis – Cell death

Answer 17

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)

Question 18

Metamorphosis – Remodeling

Answer 18

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)

Question 19

Metamorphosis – Respecification

Answer 19

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

Question 20

Metamorphosis – Regional specificity

Answer 20

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

Question 21

Regeneration

Answer 21

Reactivation of development in post-embryonic stage to restore missing or damaged tissue

Question 22

Regeneration

Four different models:

Answer 22

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

Question 23

Regeneration in flatworm —>

Answer 23

stem cell-mediated (pluripotent), dependent on morphogen gradients

Question 24

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

Answer 24

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

Question 25

Regeneration in Salamander

Answer 25

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

Question 26

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:

Answer 26

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)

Question 27

Genetic errors in development

Genetics based syndromes are generally caused by:

Answer 27

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

Question 28

Genetics based syndromes are generally caused by:

Answer 28

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)

Question 29

Environmental mechanisms

Timing of exposure to environmental agents that cause birth defects (teratogens) is important

Answer 29

environmental agents that cause birth defects = teratogens

Question 30

Thalidomide as a teratogen

Answer 30

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

Question 31

Alcohol as a teratogen

Answer 31

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

Question 32

Alcohol is thought to cause defects in neural crest cells

Answer 32

Can cause cell death by generating superoxide radicals

Question 33

Endocrine disruptors

Can interfere with hormone function is various ways:

Answer 33

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

Question 34

Diethylstillbestrol (DES)

E.g. misregulation of Mullerian duct morphogenesis by DES

Answer 34

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)

Question 35

Bisphenol A (BPA)

Answer 35

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

Question 36

Cancer as a development disease

Answer 36

Carcinogenesis can be viewed as aberrations of processes that underlie differentiation and morphogenesis

Question 37

Cancer as a development disease

MicroRNAs are being tested as a possible means of differentiation therapy –

Answer 37

treatment that uses various molecules (e.g. transcription factors, miRNA) to revert the cancer cells to differentiation instead of proliferation

Question 38

Using stem cells to implement cell-based therapies for various disorders

Answer 38

Stem cell therapy

Question 39

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

Answer 39

Induced pluripotent stem cells (iPS) are given the DNA containing WT allele (HbA)