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ANAT 381 > Ryan Lecture 6 > Flashcards

Ryan Lecture 6 Flashcards

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1
Q

Name and describe the regions of a limb from proximal to distal

A

Stylopod = humerus
Zeugopod = ulna, radius
Autopod = carpals, digits
= blocks of tissue to form continuous structure

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2
Q

Name and describe 3 critical regions in developing limb bud

A

Progress zone
Zone of polarizing activity ZPA
Apical ectodermal ridge = AER

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3
Q

Describe AER

A

REGION of thickened ectoderm
Forms at boundary between dorsal and ventral sides limb bud
Required for patterning all 3 axes of limb

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4
Q

WHAT IS required for PD axis

A

AER
Removing AER = inhibits proximal distal growth of limb bud
Progress zone wont grow or do mitosis = wont form structures

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5
Q

Describe Ffg8 expression in AER

A

Specific patterned expression = thickened region ectoderm

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6
Q

What can replace AER activity

A

Fgf bead
If remove AER but implant fgf bead = normal wing develops, gets outgrowth
Bead replaces patterning signal

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7
Q

Describe gradient along limb P-D axis

A

opposing RA-FGF gradients
Proximal = retinoic acid
Distal = fgfs/wnts
Threshold patterns= retinoic acid —> fgf = stylopod meis, Zeugopod hox11, autopod hox13

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8
Q

Describe hox expression along trunk A-P axis and limb P-D axis

A

Homeotic selector genes
Come on later in dev - for limbs

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9
Q

Describe HOX expression along Limb P-D axis

A

Domains of expression correspond to subdomains of limb

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10
Q

Describe experiment to test RA effects on limb bud P-D patterning

A

Limb bud tips transplanted to bead region of embryo - tips, distal ends of progress zone
Limb bud tips were either transplanted directly or first treated with RA
Staging = number of somites present
Untreated = see distal structures of autopod
Ra treated = in early see more proximal structures, bones they form, but tissues less competent to respond at later dev
Explanation = effect of age of limb bud tip, effect of RA, older and more distal to RA signal = less likely to be responsive

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11
Q

Describe experiments to test how FGF/wnt effects on limb bud P-D patterning

A

Untreated stage 18 mesenchyme
Stage 18 mesenchyme incubated with fgf/wnt
= see less meis1 fgf repressing proximal gene expression
Not much effect in Zeugopod, hoxa10
In autopod = maybe enhancing, hoxa13
Opposite effects = suggests gradients opposing

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12
Q

What causes mice to miss Zeugopod

A

Hoxa11/Hoxd11 deficient mice
Loses whole structure if do not have tissue to pattern them

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13
Q

What casues polysyndactayly in humans - fused digits

A

Homozygous mutation in HOXD13
Autopod region
Lost patterning of mesenchyme, maybe loss of webbing early on
= misshaped did his but dorsal ventral axis fine (can see finger nails)

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14
Q

What does AER activity require

A

Limb bud mesenchyme
Replace limb bud mesenchyme with non limb mesenchyme = from diff part embryo
AER regresses = limbs dev stops, doesn’t support maintained of AER and low levels fgf8
Indicates that patterning molecules also exist in limb bud mesenchyme

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15
Q

What is P-D specification of limb correlated with

A

Age of progression zone mesenchyme
Young progression zone into old limb buds = still grow, duplicate Zeugopod and stylopod
Old progression zone onto young limb buds = lost midsection,retains info and dominates how it develops = lose most of stylopod and Zeugopod

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16
Q

Where does AER form

A

AT BOUDNARY OF DORSAL AND VENTRAL ECTODERM

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17
Q

How does AER FORM

A

Pushes out and get out pouching ectoderm
Turns around it
Dorsal = lmx1
Ventral = en-1
AER acts like local organizer = becomes limb bud
, also get patterning info in msenchyme

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18
Q

WHAT IS expressed in dorsal domains in limb bud

A

Wnt7a expressed in dorsal ectoderm
Lmx1 - lim1 expressed in dorsal mesoderm

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19
Q

What is expressed in ventral domains of limb bud

A

En-1 (engrailed) expressed in ventral ectoderm
BOUDNARY where engrailed Meets wnt7 = fgf turns on in AER

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20
Q

Describe D-V patterning pathway in limb bud

A

OPPOSE each other = keep d and v separate and keep ridge AER
Dorsal = Wnt7a, lmx1b
Ventral = en1, bmp
En1 inhibits r-fng (—>AER formation) and Wnt7a (—> lmx1—>dorsal pattern)

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21
Q

Describe Dorsal-ventral patterning by Wnt7a

A

Lmx1b dependent dorsal ventral patterning by Wnt7a
Foot pad=ventral
If lmx1 mutant = remove form dorsal mesoderm = lose dorsal structures on dorsal and ventral =footpads

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22
Q

What happens when engrailed KO

A

Loss of ventral patterning in limb
Ventral missing so dorsal no longer repressed so takes on dorsal phenotype
Nail replaces food pad
Repress other one so drives ventral and prevents dorsal

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23
Q

What can AER also do

A

Pattern a-p axis
Addition of AER tissue cases digit duplication
Has ability to pattern and duplicate But not so much overall polarizing region
In autopod region, depends on time too
Same orientation

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24
Q

Describe ZPA

A

Not morphologically visible
Located in posterior margin fo limb bud
Found via transplantation exp then molecularly
Post = shh concentrated in ZPA

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25
Describe ZPA transplantation experiments
Front post to anterior = 2 zpa, transplant one Now = digits face each other - mirror image Change in dose shh patterns digits Mouse zpa to chick also works - source does not matter, digits look like chick digits
26
Where is Shh expressed
In ZPA
27
What can replace ZPA activity
Shh Transplantation exp = transplanting zpa or shh beads causes mirror image duplication - different from digit duplicated caused by transplanting AER
28
Describe how digit 1 response to shh signalling
Thumb, shh independent Further away from zpa
29
Describe how digits 2 and. 3 respond to shh signaling
Differentiation dependent on shh concentration - paracrine signalling Lower dose but still need it
30
Describe how digits 4 and 5 response to shh signaling
Shh dependent, time dependent - auto rise Highest exposure, most dependent
31
Describe signalling from ZPA
Dose dependent Long range ZPA MUST be in contact with AER = feedback loop
32
Describe timing of expression of fgf8 and shh
Fgf8 expressed in AER before shh expressed in zpa Aeschylus stage = formation 3 somites, = stage 16, so 4.5 hrs Shh= comes on aprox 12 hrs after fgf8 in AER
33
What regulates outgrowth of progress zone
Feedback loops between AER and limb mesenchyme regulate outgrowth of the progress zone Fgf8 = + effect on shh in ZPA, also inhibits gremlin =antagonist bmp Complicated feedback between AER ad zpa, and molecules expressed in limb bud mesenchyme
34
Describe feedback loops between AER AND LIMB MESENCHYME
Low fgf = turns on shh —> grem1 (repress bmps) Then HIGH fgf = represses grem1 so bmps increases and Goes back to low fgf, repeat Control timing and level of expression = gives differences
35
What determines limb identity
Position of fgf bead Along a-p flank Limb mesenchyme
36
What can change identity of limb
Replacing forelimb mesenchyme with hindlimb mesenchyme changes identity of limb Cells contain patterning info = how we shape bones or how muscle attaches
37
Describe what is specific to forelimb or hindlimb bud
Tbx5 = in wing bud uniquely Tbx4 = hind limb bud Pitx1 = hind limb bud, close relative of pitx2
38
Describe Tbx5 and tbx4 expression in ectopic limb buds
Also pressed in other regions Tbx5 = top half expresses, Tbx4 =bottom, not top, like post limb bud GIVES CHIMERA
39
What do Tbx5 knockout mice tell us = EARLY KO
Forelimbs do not Develop Express recombinase in this region of limb - prx1cre, Tbx5 lox/lox
40
What do Tbx5 knockout mice tell us = LATER KO
Delete only after E9.5 = forelimbs patterned normally Treat at diff days, some delay for effect tho After limb buds already formed Earlier knockout = much severe phenotype
41
What do Tbx5 knockout mice tell us =DESCRIBE EXP METHOD
Tbx flaked by lox sides Cre recombinase clips lox site and repair so tissue specific knockout Tbx5 flanked by loxP sites Cre recombinase cuts dna at loxP sites Expression of Cre is driven by prx1 promoter..limb specific, drives expression for limb protein Cre fused to estrogen receptor (piece of) ligand binding domain, so only enters nucleus when estrogen ligand present, acts as tf Introduce estrogen by gavaging pregnant moms at different days, via tamoxifen and will delect tbx5
42
DESCRIBE Exp where early ko Tbx5 and then express tbx4 or pitx1 in forelimb
If add ectopic tbx4 in forelimb bud = can rescue forelimb If add ectopic pitx1 in forelimb bud = cannot compensate,cannot rescue Tbx4 and tbx5 activate same set of target genes in developing limb bud Date suggests that tbx4/5 required for fore/hind limb bud initiation but not identity
43
Describe exp = ectopic misexpression of pitx1 in wing bud
Retrovirus expression pitx1 is injected into flank at position of forelimb bud =cause it to have more hindlimb identity, more important for hindlimb identity Suggest = pitx1 dominantly drives expression of genes needed to give you hind limb identity
44
Describe species specific patterning of limb bud
Same set of genes needed for initiating patterning Species specific events layered on top
45
Describe disrupting embryonic dev
2 haploid cells, genes and environment = lead to 1 trillion diploid cells + some haploid cells, germ cells
46
How often are babies born with birth defects
Every 4.5 mins there is a baby born in the US with a birth defect
47
What is leading cause of infant mortality
Birth defects 1 in 5 infant deaths due to birth defect - 2006 (in first 2 years life) Among top 5 causes of death between 2 and 18 y/o
48
Describe some estimated stats for embryos
20-50% of human cleavage stage embryos implant 40% of embryos that implant survive to term 2.5% live births have a recognizable birth defect, could be minor or severe
49
What accounts for neonatal death
Congenital abnormalities account for ~9% of annual neonatal deaths Preterm birth is a direct cause of 35% of all neonatal deaths Cost = huge if severe birth defect
50
Describe embryo vs fetus = EMBRYO
Period of dev during which organism does not resemble adult First 8 weeks in humans All major organ systems established
51
Describe embryo vs fetus = FETUS
Period of dev where organism resembles adult Weeks 9-40 in humans Growth and refinement = cells differentiation
52
WHEN IS risk of defects highest
Organogenesis 3 weeks before gastrulation = wont notice but die Formation of organs= period of max sensitivity to abnormal dev - 2-8 weeks, heart defects, spina bifida Growth and maturation of organ systems = 8-38 weeks, affect differentiation of systems, fetal development
53
Describe critical times in prenatal development
Major congenital abnormalites Highly sensitive period bc that is when they develop Death of embryo and spontaneous abortion common during weeks 1-2 = periof of dividing zygote, implantation, bilaminar embryo
54
Describe period of sensitivity during dev
Heart = weeks 3.5 to 9 Eyes = weeks 4.5 to full term Cns =weeks 3 to full term Ears = 4.25 to 20 Teeth = 6.75 to full term Palate = weeks 6.75 to 16 Upper limbs = 4.5 to 9 External genitalia = weeks 7 to full term Lower limbs = weeks 4.5 to 9
55
Describe genetic heterogeneity
Similar phenotypes casues by diff genes/pathways Mutations
56
Describe phenotypic heterogeneity
Same mutation cases diff phenotypes in diff people One gene among many - also second hit Also environment = mother gets disease of malnourished = can affect embryo, Matt ion makes embryo more susceptible
57
Name causes of congenital anomalies/birth defects
Genetic factors Environmental factors Stochastic Most =dont know
58
Describe causes of congenital anomalies/birth defects = genetic factors
Chromosomal - numerical and structural Gene mutations
59
Describe causes of congenital anomalies/birth defects = environmental factors
Teratogens - disruptions Physical environment = deformations
60
Describe causes of congenital anomalies/birth defects = stochastic
Wild type genes, favourable environment + bad luck Protein synthesis fluctuations Random and cause differences
61
Name 4 structural changes in dev
Dysplasia Deformations Malformations Disruptions
62
Describe dysplasia - structural changes in dev
Abnormal organizer of cells into tissues and its morphological result Abnormal growth mostly benign
63
Describe deformations - structural changes in dev
Caused by mechanical forces = psychical environment, disrupt how formed
64
Describe malformations - structural changes in dev
Genes Caused by intrinsically abnormal developmental process Abnormal form beginning Defect of a morphogenetic or whole developmental field, particular step Something is off
65
Describe disruptions - structural changes in dev
Teratogens Casues by interference of an originally normal process. - disrupted Cannot be inherited, genotype may predispose response of embryo But genotype not cause of defect
66
Describe an ex of limb deformation - clubfoot
Potentially caused by oligohydraminos - low levels of amniotic fluid Not enough fluid for fetus to move around Pushed into position, soft = casues bones to bend, can be corrected after birth
67
Describe ex of limb malformation = holt oram syndrome - gen
Gene originally linked to 12q21.2-q22 Due to mutation tbx5 Upper limb anomalies, -/+ atrial septal defect in 75%, forelimb affected Limb anomalies may be limited to thumb or more extensive
68
Describe ex of limb malformation = holt oram syndrome - acc mutations
Autosomal dominant disorder with complete penetrance - everyone will have same phenotype, but maybe some variations Null alleles have more extensive skeletal and cardiac abnormalities - no protein Missense mutations have moderate phenotypes = protein less functional, so less severe than no protein
69
Give ex of limb disruptions due to thalidomide
1956 - used to treat influenza, then as sedeative then to treat nausea vomiting during pregnancy Classic thalidomide embryopathy = range of defects, depends on dose, include limb anomalies (phocomelia or amelia), congenital heart defects, ear abnormalities, dudodenal atresia, aplasia of thumbs
70
Give ex of limb disruptions due to thalidomide - timing
Limb disruptions from thalidomide occurs early during limb dev - tbx5 malformations= major congenital anomalies - weeks 1-8 Limb deformations - club foot = occur later during dev, functional defects and minor anomalies - weeks 9-38
71
Describe summary of limb congenital anomalies
Limb malformations can be caused by mutations in signaling molecules (SHH, FGFs and BMPs) or transcription factors (Hox, Tbx). Limb development is sensitive to teratogens (e.g. thalidomide) that can cause limb disruptions. Limb deformations (e.g. club foot) occur at later time points during fetal development.
72
What are teratogens
Greek origin Teratos = monster or marvel Disrupt normal processes Agent to factor that affects morphogenesis, dev aand differentiation through cell death, failed cell interactions or alterations of cell movements - disrupt many things Usually applied to environmental causes like drugs, chemicals and viruses Different teratogens may produce common effects, ex=hot tubs linked to neural tube defects
73
Describe discovery of teratogens - history
<1940s = thought embryos were protected from environment by extra embryonic and fetal membranes, thought it was super safe 1941= rubella virus, 1st documented case that an evironental agent could produce disruptions Silent spring by Rachel Carson 1962, DDT Thalidomide - summer 1962 Effect of chemicals becomes clear
74
Name the 3 considerations - teratogens
Critical periods of development Dosage of drug/chemical Genotype of embryo
75
Describe consideration of teratogens = critical periods of dev
Early vs late effects - is embryo or fetus sensitive at that time May extend into postnatal periods = teeth, brain
76
Describe consideration of teratogens = dosage of drug/chemical
Dose used in animals if often way >> than human exposures, mouse and rats have diff metabolism Need to establish a dose response curve
77
Describe consideration of teratogens = genotype of embyro
Response varies based on genotype of embryo Like variations of proteins that metabolize the products
78
Describe why/why not drugs are tested on pregnant women
In humans, unless a drug is intended to treat a condition unique to pregnancy - studies systematically attempt to exclude women and ensure that women of child bearing age do not become pregnant during period of drug exposure - so no risk In humans = unethical to conduct trial to assess teratogenicity Oh 172 fda approved drugs between 2000 and 2010 = 97.7% majority had an undetermined teratogen risk in human pregnancy 73.3% had no data available -regarding safety in pregnancy
79
Name main exs of known teratogens
Drugs = alcohol (tied to genotype, many diff genotypes and responses), isotretinoin (retinoic acid), thalidomide Chemicals= endocrine disrupters, like brith control pills, polluted water makes fish change sex Infections = rubella virus
80
Name all teratogens
Drugs = alcohol, androgens, busulfan, cocaine, DES, isotretinoin, lithium carbonate, methotrexate, phenytoin (dilantin), tetracycline, thalidomide, trimethadione, valproic acid, warfarin Ionizing radiation Hyperthermia Chemicals = methyl mercury, PCBs, endocrine disrupters Infections = cytomegalovirus, herpes simplex virus, human immunodeficiency virus, human parovirus B19, rubella virus, toxoplasma gondii, treponema palladium, varicella virus
81
Describe thalidomide - conclusions
Teratogenic effects casued withdrawn from use 1961-1962 Now being used to treat hiv and cancer Sensitive periof between 27 and 40 days after conception Maybe damage neural crest cells
82
What become mandatory after thalidomide incident
Testing of drugs in pregnant experimental animals
83
What can ethanol do
Induce congenital abnormalities Alcohol is most devastating teratogen with respect to frequency and cost to society Prevalent, many defects Neural tube defects = 1st trimester pregnancy Fetal alcohol syndrome = hAPPENS LATER, period of dev
84
Describe symptoms of fetal alcohol syndrome
A baby with fetal alcohol syndrome may have the following symptoms: Poor growth while the baby is in the womb and after birth Decreased muscle tone and poor coordination Delayed development and problems in three or more major areas: thinking, speech, movement, or social skills Heart defects such as ventricular septal defect/atrial septal defects Characteristic craniofacial features
85
Describe ethanol induced dysmorphology
Treated on gestational day 7 = Embryos lose midline structures and eyes move towards Center Get proboscis - almost Cyclopia Animal study
86
Describe FAS - fetal alc syndrome stats
Craniofacial structural defects 2001 estimate = 1out of evert 650 Current estimates higher = up to >1%
87
Describe ethanol induced dysmorphology in human babies
Phenotypes range from relative mid fetal alcohol syndrome, cognitive effects and affects ability learn to holoprosencephaly = HPE, since nostril TO HPE + CLEFT LIP (V SERIOUS)
88
What does too much vit a do
TERATOGENIC Retinol = morphogen Effects = very bad, need to be on 2 forms of birth control before can get higher dose retinol = iPLEDGE PROGRAM
89
What can also induce holoprosencephaly
Retinoic acid, cylopia = lost central structures
90
Describe congenital anomalies casues by isotretinoin
Increased risk of spontaneous abortions Hydrocephaly (enlargement of the fluid-filled spaces in the brain) Microcephaly (small head and brain) Mental retardation Ear and eye abnormalities Cleft palate and other craniofacial abnormalities
91
Describe iPLEDGE PROGRAM
Roche Pharmaceuticals had shown birth defects in animals. FDA approved Accutane in 1982 with implementation of voluntary risk management to prevent pregnant women from using drug – not successful! Lammer et al., 1985 followed 59 women who elected to remain pregnant after RA exposure: 12 spontaneous abortions; 21 major observable anomalies In 2005 FDA started iPLEDGE a MANDATORY risk-management program that all patients, including men, who take isotretinoin, must participate to achieve two goals (2): To ensure that no pregnant woman starts taking isotretinoin To ensure that no woman taking isotretinoin becomes pregnant Must use at least 2 forms of birth control for 1 month before, during and 1 month after [multiple pregnancy tests].
92
DESCRIBE ethical considerations
Animal models Stem cells Organoids Impact of research on planetary health What is next?
93
Describe ethics of embryology - Gen conc
7 YEARS AGO = one health WHO ORGANIZATION = integrated, unifying approach to balance and optimize the health of people, animals and the environment. It is particularly important to prevent, predict, detect, and respond to global health threats such as the COVID-19 pandemic. Could only culture to 14 days = just before gastrulation On may 4th 2016 = 2 groups recorded that they had sustained human embryos in vitro for 12-13 days What are responsibilities, when does life begin Organoids = take induced pluripotent stem cells and grow tissues Future considerations
94
DEFINE PROGRESS ZONE
Progress zone = zone of highly proliferative mesenchyme that fuels limb outgrowth, progresses outwards, underlines ectoderm
95
DEFINE ZONE OF POLARIZING ACTIVITY
Zone of polarizing activity (ZPA)= located in posterior mesenchyme of limb bud - important for pattering a-p or limb digit
96
DEFINE APICAL ECTODERMAL RIDGE
Apical ectodermal ride (AER)= formed at boundary of dorsal and ventral ectoderm, thickened

ANAT 381 (24 decks)

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