Block I Flashcards
What is the scope of embryology?
Study of development of an organism from fertilization of the ovum (single cell stage) through the period of organogenesis
What is the time frame for en embryo?
Embryo: from single cell 8th week of human development = organogenesis
Fetus time frame?
Fetus: 9th week 38th week (birth)
What is organogenesis?
Where primoriums of organs starts to develop
What did karl ernst von baer (XIX) established?
Father of modern embryology:
1) Described the oocyte and cleaving zygote, blastocysts and stages of embryonic development. “established that mammals develop from eggs.”
2) Determined that general characteristics precedes specific ones: Phylotypic stage in embryonic development
father of medicine
Hippocrates
Aristotle
Founder of embryology; he thought that sperm contained a tiny human being inside.
Leonardo da Vinci
established measurements of prenatal growth
observed sperms under microscope
Anton van Leeuwenhoek
eggs come from the ovaries
regnier de Graaf
Nobel prize in Medicine 1935, primary induction [gastrulation]
Hans Spemann
Lewis, Nusslein-Volhard and Wieschaus
(Nobel prize in Medicine 1995)- discovery of genes that control embryonic development i.e., gap, pairrule, segment-polarity and homeotic genes
Describe blastocyst stage
Cell proliferation stage; first 2 weeks. from zygote to morula, blastocyst and formation of bilaminar embryonic disc.
Describe embryo stage
Weeks 3-8; constitute the dynamic period of gastrulation, folding of embryo and the formation of all the organ systems.
Describe fetal stage
Months 3-9 (full term); period of growth of all major structures that have already appeared.
Explain birth defects in the first 2 weeks
In the blastocyst period, birth defects do not originate since body systems and structures have not yet developed. teratogens usually cause the loss of the entire conceptus. spontaneous miscarriages
What is the conceptus?
embryo + placental membranes
Explain birth defects in the embryo period
Most active period of development and differentiation, thus, is the most vulnerable to mjor birth defects since teratogens interrupt development and cause birth defects
Explain birth defects in the fetal period
Birth defects in this period are usually not as severe or obvious and include small size, mental retardation, defects in the eyes, ears, teeth and external genitalia; less teratogens.
What are the first early embryonic developmental stages?
Morula
Blastula
Gastrula
neurula
WHen does the early embryonic develop. stages start?
Repeated mitotic divisions (30 hours after fertilization)
What are blastomeres?
Increased # of cells together with a decrease in size
When does the morula happen?
After the 8-cell stage, cell compaction occurs (12-32 cells = morula)
identify and what happens after this stage?
2 cell stage division;
4 stage cell division > 8 cell stage division > morula > early blastocysts > late blastocyst
What is blastocyst?
Fluid-filled space blastula or blastocyst
What is gastrula?
characterized by formation of
the 3-germ layers
Identify; what does the red circle give origin to?
PLacenta
identify
When does the morula happen?
3 days after fertilization
What is neurula?
stage in which neurulation occurs (development of nervous system) forming primarily the neural tube
What are the 3 germ layers that form in the gastrula?
ectoderm, mesoderm, endoderm
Identify
Gastrula
Where does gastrulation start?
In the dorsal/causal most posterior part of embryo with cells from mesoderm that evaginate and give origin to endoderm.
What does primitive node do?
Provide growth factors to have all tissues neede din th eembryo; Organizer = primitive knot/node (Hensen’s node in humans) Will induce the notochord
Identify
identify
iDENTIFY
what does the notochord do?
-Embryonic specific structure that defines the primordial axis of the embryo
-Defines the phylum of chordates: Urochordates and Vertebrates
-Gives some rigidity
-Is the basis of development of the axial skeleton
-Sends signals to surrounding tissue
When does the notochord disappear?
It disappears when the vertebral bodies form (4th wk)
How does the notochord transforms into as adults?
It degenerates and disappears, but it persists as the nucleus pulposus (NP) of each intervertebral disc.
What is chordoma?
tumors formed by vestigial remnants of the notochord
What are pharyngeal (branchial arches)?
Condensation of mesoderm in the cranial region will give rise to transient structures to develop vertebrate head structures. Origin of head and neck
Which cells migarate in the paharyngeal arches
mesoderm cells and neural crest cells (migrate dorsal-lateral)
What are the divisons of arch 1?
Maxillar region and mandibular region
Neural crest cells originate from?
Neural tube
Explain the neural crest cells migration
from neural tube semi open in dorsal part; when it closes in dorsal part, cells detach and migrate dorsal/lateral to form different structures including giving rise to some arches.
Mandible bones arise from?
neural crest cells that migrate to the 1st pharyngeal arch.
What structures originate from 4th - 6th arch cartilages?
-greater cornu (horn) of hyoid bone
What structures originate from Third arch cartilage?
Thyroid and cricoid cartilage
What is induction?
Process in which one group of cells or tissues causes another set of cells or tissues to change their fate.
How does induction work?
One cell type or tissue is the inducer that produces a signal, and one is the responder to the signal. It has to be a competent cell Competence- the capacity to respond to the signal (i.e., receptor expression).
What is essential for differentiation?
Crosstalk between the two cell types or tissues (induction)
How are cells in the induction period?
poorly differentiated; cells with high grade of proliferation; induction works by making these cells less proliferative and more differentiated with markers
Explain
Example: Epithelial-mesenchyme interactions
Limb mesenchyme with overlying ectoderm to produce limb outgrowth and differentiation
Primary induction-neural tube formation. Notochord induces overlying ectoderm to form neural plate (neuroectoderm).
What are some inductors that form the neural tube?
FGF-B upregulation (promotes neural plate formation
BMP-4 inhibition because promotes epidermis
Shh
Retinoic Acid
What are the types of intercellular communication?
Paracrine
Juxtacrine
cell-cell
What is the paracrine?
secreted inductor molecule; Ligand (soluble factor)/receptor (Growth & differentiation factors [GDF], morphogens) and have effect of cell that responds
What is juxtacrine?
-Receptor/membrane bound ligand in adjacent cells i.e., Notch/Delta
-Extracellular Matrix-dependent
mediated interactions by extracellular matrix or receptors in cells interacting.
What is cell-cell intercommunication?
direct contact for example: Gap junctions (connexins)
Connexins are proteins that bound cells togetehr.
What is cell differentiation?
Cells become specialized by means of cell signaling, environmental influences (secreted factors, morphogens, etc.).
What is morphogenesis?
Processes by which order is created in the developing organism.
Order is achieved through cell differentiation into tissues, organs, and the whole system.
What are the major morphogenetic processes in early embryology?
-Cell division
-Condensation
- Cell Death
- Migration
- Matrix secretion and degradation
- Growth
What do Transcription factors do?
They regulate gene expression by activating it or repressing it.
Provide examples of transcription factors
-Hox/Homeobox proteins
-Pax
-Basic Helix-loop-Helix
What do Pax proteins do?
Important for development of eye; defects here can cause ocular disorders.
What do basic helix-loop-helix do?
Regulate transcription
Where did Hox/Homeobox proteins were discovered?
first discovered in Drosophila melanogaster.
How many base pairs does hox/homeobox proteins have and what do they encode?
All the Hox genes contains 180-base-pairsequence,
the homeobox, which encodes a 60-amino-acid homeodomain composed of 3 alpha
helices.
Where does the helix bind in the hox/homoeobox proteins?
The third helix binds to DNA sites in the promoter of their target genes
what does mutations in these hox/homeobox genes lead to?
Mutations in these genes of the HOM-C complex lead to dramatic phenotypes (homeotic transformation) ie., Antennapedia gene (legs instead antennae in head)
What does defects in HOX1A lead to in humans?
impair human
neural development
Why are morphogens important?
They generate concentration gradient and send signals to aid migration, differentiation and growth factors.
What are morphogens?
Diffusible molecules that specify which cell type will be generated at a specific anatomical location
What is the function of morphogens?
Morphogens also direct the migration of cells and their processes to their final destination.
Where are morphogens found?
Many morphogens are found in concentration gradients in the embryo and expressed in opposing
gradients in the dorsoventral, anteroposterior, and mediolateral axes
By what does the fate of a specific cell is determined?
by its location along these gradients in the morphogens
What is Retinoic acid?
A morphogen derived from vitamin A and important for anteroposterior axis
What does insufficient retinoic acid lead to?
favorable caudal structures
What does high concentrations of retinoic acid promote?
cranial structures in 3’ end anterior early
Why is Retinoic acid important?
RA are powerful teratogens, especially during the first trimester.
What are hedgehogs?
Morphogens that generate concentration gradient and send signals to aid in cell differentiation pathways, migration and growth.
What morphogen was the the first mammalian ortholog of the Drosophila gene hedgehog?
Sonic hedgehog (Shh)
Mention the 3 types of hedgehog morphogens
Sonic, Indian, Desert
Where do motor neurons from nervous system originate from?
floor of neural tube
mutations in SHH or its receptor can lead to?
Holoprosencephaly- fused cerebral hemispheres is a congenital disorder linked to mutations in SHH or its receptor. When they fuse more medial.
Where is SHH secreted?
Shh is secreted at high levels by the notochord, thus providing high levels in the floor of the neural tube (promoting motor neurons
What is the primary receptor for SHH?
Patched (PTCH in human, PTC in mouse)
What can abberantly activate hedgehog signaling pathway
Some cancer types
Explain this complex
Presence of Shh- activation of signal transduction. When shh is [resent, suffers a cut and cholesterol molecule binds, inhibits and activates, they interact and the complex of SuFu with Fu can bind, the GLI get liberated and activated and with other molecules activates transcription.
Explain this complex
Absence of Shh- inactivation of signal transduction.
If there is absence of SHH, its receptor, PTCH, cannot interact with other receptor called SMO. If that interaction doesnt take place, the other complex cannot bind to SuFu (Suppressor of fused negative regulator. When that doesnt occur, the GLI transription factor modifies, goes to the nucleus and inhibits gene expression.
what is TGF-B?
Transforming Growth Factor ℬ a morphogen important for the migration and axonal guidance.
Why is TGF-B important?
TGF-ℬ signaling is a tumor suppressor factor and inhibits cell proliferation. Its dysregulation has been implicated in cancer
Explain the comoplex
In absence of TGF, TBR-II is phosphorilated, so phosphorilation of TBR-II doesnt occur and phosphorilation of trasncription complexes dont occur either; they dont go to the nucleus thius no gene expression.
On the other hand, if TBR-II phosphorilates TBR-I, it phosphorilates R-Smad complexes which are transcription factors that can pass to the nucleus and activate gene expression.
What is Receptor tyrosine kinases (RTK)?
group of membrane-bound receptors that play an important role in the normal function of cells by
phosphorylating tyrosine residues on intracellular substrate proteins
How do TGF-B work?
TGF-B binds to transmembrane kinase receptors (RTK) to phosphorylate intracellular receptor-associated
Smad proteins (R-Smads). Smads complexes regulate target gene expression in the nucleus
What is fibroblast growth factor and some of its roles? (FGF)
A morphogen that Influences morphogenesis in embryonic development. Some of its roles include: cell migration, differentiation, survival, apoptosis, induction, among others and may form a concentration gradient over the developing embryo.
How was FGF discovered?
Discovered by its role in stimulating cell growth and proliferation of mouse fibroblasts
How many receptors does FGF have?
four isoforms FGFR1-R4
Tyrosine kinases can phosphorylate in?
Tyrosine residues
What do heparan sulfate proteogylcans do?
(in extracellular matrix) modulate FGF diffusion and gradient formation
In what embryological development is FGF important?
When formation of capillaries and blood vessels start to form/
What is Wnt/b - catenin pathway>
allow catenins inside the cell to go to the nucleus and activate, along with a transcription factor, gene expression.
Explain the pathway
Wnt can interact with its receptor Fzd and also with the co-receptor LRP5/6. This promotes the complex that B-catenin doesnt phosphorylate making B-catenin accumulate in the cell and goes to the nucleus to activate geen expression.
On the other hand, in Wnt absence, there is no interaction of receptor with co-receptor and all the trabscription factors pomote B0catenin to phospjhorylate with the promotion of an enzyme, the signal is to degrade b-CATENIN; Thus, it cannot bind to TCF factor and since TCF factor is a suppressor and needs catenin to activate transcription, it suppresses the expression.
What does Wnt direct?
Wnts direct cell polarity, proliferation, apoptosis, cell fate and morphogenesis (patterning the CNS, the gut,
the respiratory and circulatory systems, among others
What cancer does Wnt promote?
Also play role in tumor formation (colorectal cancer in humans)
Is notch delta signaling pathway a morphogen?
No
In what does notch delta signaling pathway depend?
cell-cell interaction, cell with receptor notch and other cell with ligand delta/jagged
Explain pathway
Notch/Delta Signaling Pathway
Ligand-receptor interaction triggers proteolytic events leading to the release of the Notch Intracellular domain (NICD). NICD translocates to the nucleus for activation of the transcriptional complex, activating target genes that inhibit proliferation, and thus
maintaining the progenitor state of the cells.
Activates genes that inhibit differentiation leave cells in pluripotent stage, this is called lateral inhibition.
What is the notch delta pathway important for?
This pathway is integral for cell fate determination, maintenance of stem-cell niches (lateral inhibition), apoptosis, and differentiation
What are notch proteins?
Notch proteins are single transmembrane receptors that interact with membrane-bound Notch ligands (i.e., Delta/Jagged) on adjacent cells
What are cadherins?
Cell Adhesion Molecules; (calcium-dependent adhesion)
In what are cadherins involved?
cell recognition, signaling, communication, morphogenesis, angiogenesis,
whY are cadherins important?
They attach to each other and create stiffness and strong tissues due to anchorage.
What is Epithelial-Messenchymal transition (EMTs)
Acquisition of mesenchymal features from epithelial cells and occurs in gastrulation during normal embryonic development for mesoderm, notochord etc. Also seen in adult tissue regeneration
What happens if theres a disregulation in EMTs?
Cancer progression.
EMT allows solid tumors to become more malignant, invasive & metastatic.
Histologic features connecting secondary metastatic tumors to the primary is called mesenchymal epithelial transition (EMT).
Cadherins are important markers for the expression of EMT (others are TFs and enzymes [MMPs])
What is Messenchymal-Epithelial transition (METs)?
Metastatic tumor cells at distant sites undergo MET (may be found at different transition stages).
§ Mixed expression of epithelial and mesenchymal markers
§ EMT or MET modulation is an important approach to avoid metastasis
What is epigenetics?
inherited changes that affect egen expression as a result of modification to the DNA but not to the sequence, by methylation or acetylation
what is methylation and hypomethylation?
methylation:
add methyl groups at cytosine residues which results in reduction of gene expression (silencing) by prohibiting transcription factors by going into the promoter.
Hypomethylation: poor methylation, gene more open to promoter area so that transcription factors can enter, resulting in gene over expression.
what is acetylation?
add acetyl groups to histones (proteins around which DNA is coiled). Acetylated DNA is less tightly bound to histones = more open access for transcription
How is embryonic age calculated?
It is difficult to determine exactly when fertilization(conception) occurs because the process cannot be observed in vivo (within the living body). Physicians calculate the age of the embryo from the first day of the last normal menstrual period (LNMP). This is the gestational age, which is about two weeks longer than the fertilization age because the
oocyte is not fertilized until about two weeks after the preceding menstruation.”
When does gestational age begin?
During the day 1 of last menstrual cycle. Last normal menstrual period (LNMP)= gestational age, which is
two weeks longer than the fertilization age.
What are stages in embryonic age calculation?
Stages during early embryonic development begin at fertilization.
What happens in stage 1?
fertilization
What happens in stage 2?
Zygote divided and morula appears
What happens in stage 3?
Early and late blastocyst form
What happens in stage 4?
Implantation begins
What are totipotent cells?
Cells in Zygote and early morula capable of differentiate into any cell type. Ethical issues.
What are Embryonic stem cells (ES)
are derived from the inner cell mass of the embryo (blastocyst) and are pluripotent.
What are pluripotent cells?
these cells have lost the capability of differentiating like totipotent but can form virtually any cell or tissue type, they have the potential of curing a variety of diseases, including diabetes, Alzheimer and Parkinson diseases, anemias, spinal cord injuries, and many others. Ethical issues.
What are Adult stem cells?
Adult tissues contain stem cells that may also prove valuable in treating diseases. These cells are restricted in their ability to form different cell types and, therefore, are multipotent, not pluripotent… Less ethical issues
Where are gametes derived from?
Derived from Primordial Germ Cells (PGCs)
Where are PGCs found?
during 2nd week in the wall of yolk sac
what is the main function of the yolk sac?
provide nutrients and transfers nutrients to embryo, since embryo at the beginning is not connected to placenta.
Where do PGCs come from?
-PGC’s come from the ectoderm (posterior part
of primitive streak IN CAUDAL/DORSAL PART).
-Then cells migrate to the endoderm, allantois, and
wall of yolk sac.
-Cells undergo mitosis (proliferation)
Where and when do PGCs migrate to?
PGCs migration to the developing gonads (genital ridge) during the 4th week to the genital ridge which is the primordium of gonad
What is Spermatogenesis?
is the process of producing sperm with half the number of chromosomes (haploid). The germ cells progress from the diploid to haploid state and then change their shape to become spermatozoa.
where does gametogenesis (spermatogenesis) take place?
In the seminiferous tubules
In what phases is male gametogenesis divided?
- Spermatogenesis
- Meiosis
- Spermiogenesis
What happens in spermatogenesis?
- PGCs (46;2N) in the testes remain dormant until puberty. At puberty, these cells differentiate into type A spermatogonia (46, 2N; initiation of spermatogenesis). Less differentiate stage.
- Type A spermatogonia undergo mitosis (spermatocytogenesis) to maintain a continuous supply of stem cells throughout the reproductive life of the male. Type B spermatogonia (46;2N) produces after the last division of Type A cells.
What happens in meiosis?
- Type B spermatogonia divide to form primary spermatocytes 46;4N (not meiosis)
- Primary spermatocytes complete meiosis I and produce two secondary spermatocytes
(23;2N) - Secondary spermatocytes complete meiosis
II to form four spermatids (23;1N)
What happens in spermiogenesis?
- Series of changes that transform spermatids
into spermatozoa - Includes acrosome formation,, nucleus condensation, formation of the head, neck and tail
~ 74 days from spermatogonia to spermatids
~ 300 millions sperm cells/day
Cytokinesis is incomplete-cytoplasmic
bridge
What is an acrosome?
acrosome (important organelle for fertilization) which covers half of the nuclear surface and contain enzymes to assist in penetration of the egg
Identify
What stertoli cells, where are they located and their function?
surround spermatogonia and spermatids in the gonads.
They are located in the basement membrane of the seminiferous tubules.
They provide nutrients, support, as well as protection
How to stertoli cells work?
Sertoli cells respond to Follicle Stimulating Hormone
(FSH)-for synthesis of androgen receptor [important for leydig cells that produce testosterone so if there is testosteroe, the sertoli cells can respond to the receptor]
Androgens binds to Sertoli cells to promote
spermatogenesis
Release from the Sertoli cell = spermiation
(determinant for sperm count in the ejaculate) basically liberated the sperm
From what does sertoli cells derive?
Interstitial cells
What do leydig cells respond to?
Respond to Luteneizing Hormone (LH) produced by pituitary glad, to produce testosterone
Where are leydig cells located and how do they change?
Found between seminiferous tubules-close to blood vessels.
Fetal Leydig cells degenerate after birth, but during
puberty, Leydig cells re-differentiate from connective tissue
Are spermatozoa motile?
Spermatozoa are nonmotile during storage in the epididymis, but become motile in the ejaculate.
What is female gametogenesis?
Oogenesis;
PGCs (46;2N) migrate to the developing gonads (ovaries) during the 4th week.
Once in the gonads, germ cells differentiate into
oogonia
Where does the blastocyst implant?
Edometrium
Where does fecundation occur?
ampulla
What happens when primary oocyte enters prophase I?
Some enter meiosis I and arrested in prophase I
What happens to the female fetus in the womb at 4 months old?
Oogonia in clusters in the cortical part of the ovary
What happens to the female fetus in the womb at 7 months old?
All oogonia transformed to primary oocytes
What happens to the female newborn?
No oogonia present
No more primary oocyte formation after birth and arrested in prophase I until ovulation
what are the Flat epithelial cells in a newborn female?
secrete oocyte maturation inhibitor factor (OMI)
how many primary oocytes remain from birth to puberty?
40,000