Limb Development and Disrupting Embryonic Development

Question 1

Each of the following limb development regions is responsible for which part?
a. Stylopod
b. Zeugopod
c. Autopod

Answer 1

a. Humerus
b. Ulna and radius
c. Carpals and digits

Question 2

What are the critical regions in the developing limb bud?

Answer 2

Progress zone, zone of polarizing activity (ZPA), apical ectodermal ridge (AER)

Question 3

Where is the ZPA located?

Answer 3

Posterior mesenchyme of the limb bud

Question 4

Where is the AER located?

Answer 4

At the boundary of dorsal and ventral sides of the limb bud

Question 5

AER is required for patterning which axes of the limb bud?

Answer 5

Proximal-distal, dorsal-ventral, anterior-posterior

Question 6

What can replace the AER activity?

Answer 6

Implantation of FGF bead

Question 7

RA concentration is higher on the __________ axis and Fgf/Wnt concentration is higher on the ___________ axis

Answer 7

Proximal; distal

Question 8

Which genes are linked to the stylopod, zeugopod and autopod?

Answer 8

Meis for stylopod, Hox11 for zeugopod and Hox13 for autopod

Question 9

What is RA responsible for in limb bud PD patterning?

Answer 9

RA activates Meis genes and promotes proximal formation of the limb bud

Question 10

What is FGF/Wnt responsible for in limb bud PD patterning?

Answer 10

FGF initiates Hox13 genes and promotes distal formation of the limb bud

Question 11

Hoxa11/Hoxd11-deficient mice are missing which limb part?

Answer 11

Zeugopod

Question 12

In humans, homozygous mutation in Hoxd13 causes which disorder?

Answer 12

Polysyndactyly (fused digits)

Question 13

What does AER activity require?

Answer 13

Limb bud mesenchyme

Question 14

PD specification of the limb is correlated with what factor?

Answer 14

The age of the progress zone mesenchyme

Question 15

___________ and ___________ is expressed in dorsal ectoderm, ___________ is expressed in ventral ectoderm

Answer 15

Wnt7a; Lmx1; En-1

Question 16

A loss of Lmx1 causes what effect?

Answer 16

Ventralized dorsal side, causing two ventral sides

Question 17

Knockout of Engrailed causes what effect on the limb?

Answer 17

Loss of ventral patterning

Question 18

Addition of AER tissue to the forelimb mesenchyme causes what effect?

Answer 18

Digit duplication

Question 19

ZPA transplantation of mouse ZPA to chick causes what effect?

Answer 19

Formation of digits

Question 20

What is expressed in ZPA?`

Answer 20

Shh

Question 21

Transplanting ZPA of Shh beads causes what effect?

Answer 21

Mirror image duplication

Question 22

Identify the response to Shh signaling to the digits
a. Shh independent
b. Differentiation dependent on Shh concentration (paracrine)
c. Shh-dependent; time-dependent (autocrine)

Answer 22

a. Digit 1
b. Digits 2 and 3
c. Digits 4 and 5

Question 23

(Fgf8/Shh) is expressed in the ZPA after (Fgf8/Shh) is expressed in the AER

Answer 23

Shh; Fgf8

Question 24

What is the mechanism of FGF activating Shh with the activity of Grem1?

Answer 24

Grem1 stimulates FGF when FGF is low
High FGF stimulates Shh expression and represses Grem1 activity
Low Grem1 activity decreases FGF expression

Question 25

What determines limb identity?

Answer 25

Limb mesenchyme

Question 26

Tbx5 is expressed in which limb?

Answer 26

Wing limb

Question 27

Tbx6 is expressed in which limb?

Answer 27

Leg limb

Question 28

Early knockout of Tbx5 causes what effect?

Answer 28

Forelimbs do not develop

Question 29

Later knockout of Tbx5 after E9.5 causes what effect?

Answer 29

Forelimbs develop normally

Question 30

What happens if Tbx5 is knocked out and replaced with Tbx4 or Pitx1?

Answer 30

Ectopic Tbx4 in forelimb bud led to normal development of forelimb Ectopic Pitx1 in forelimb bud led to no forelimb development

Question 31

Tbx4/5 are required for forelimb/hindlimb bud _________, but not identity

Answer 31

Initiation

Question 32

Pitx1 is important for the _____________ bud development

Answer 32

Hindlimb

Question 33

Every _______ minutes, there is a baby born in the US with a birth defect

Answer 33

4.5

Question 34

What is the percentage of human cleavage-stage embryos implanting?

Answer 34

20-50%

Question 35

What is the percentage of the survival of embryos that implant?

Answer 35

40%

Question 36

What is the percentage of live births that have a recognizable birth defect?

Answer 36

2.5%

Question 37

Congenital anomalies account for what percentage of annual neonatal deaths?

Answer 37

9%

Question 38

Identify the description to either embryo or fetus a. First 8 weeks in humans b. Weeks 9-40 in humans c. Period of development during which the organism does not resemble the adult d. Growth and refinement

Answer 38

a. Embryo b. Fetus c. Embryo d. Fetus

Question 39

When is the risk of defects highest?

Answer 39

Organogenesis

Question 40

What are the periods of sensitivity for abnormal development in the CNS, upper and lower limbs?

Answer 40

CNS: Weeks 3 to full term Upper and lower limbs: Weeks 4 1/2 to 9

Question 41

What is genetic heterogeneity?

Answer 41

Similar phenotypes caused by different genes

Question 42

What is phenotypic heterogeneity?

Answer 42

Same mutation causes different phenotypes in different individuals

Question 43

What are some causes of congenital anomalies/birth defects?

Answer 43

Genetic factors, environmental factors, stochastic factors

Question 44

Dysplasia is an abnormal organization of cells into ___________ and its morphological result

Answer 44

Tissues

Question 45

Deformations are caused by what factors?

Answer 45

Mechanical forces or physical environment

Question 46

Malformations are caused by what factor?

Answer 46

Intrinsically abnormal development process

Question 47

Disruptions are caused by what factor?

Answer 47

Interference of an originally normal process

Question 48

Clubfoot is potentially caused by _____________

Answer 48

Oligohydraminos

Question 49

What is the name of the limb malformation caused by a mutation in Tbx5 and characterized by upper limb anomalies?

Answer 49

Holt-Oram Syndrome

Question 50

Which drug was used to treat influenza, as a sedative and to treat nausea and vomiting during pregnancy?

Answer 50

Thalidomide

Question 51

What limb disruption is caused by the use of Thalidomide?

Answer 51

Upper limb anomalies

Question 52

Limb disruptions occur _________ during limb development and limb deformations occur ____________ during limb development

Answer 52

Early; later

Question 53

What is an agent that affects morphogenesis, development and differentiation through cell death, failed cell interactions or alterations of cell movements?

Answer 53

Teratogen

Question 54

What are 3 considerations of teratogens?

Answer 54

Critical periods of development, dosage of the drug and genotype of the embryo

Question 55

What are other teratogens that exist?

Answer 55

Isotretinoin, alcohol, endocrine disruptors, Rubella virus

Question 56

How are the effects of thalidomide tested?

Answer 56

Testing of drugs in pregnant experimental animals

Question 57

What is the syndrome caused by fetal exposure to alcohol?

Answer 57

Fetal alcohol syndrome

Question 58

What are the symptoms of fetal alcohol syndrome?

Answer 58

Poor growth, decreased muscle tone and poor contraction, delayed development and problems in thinking, speech, movement or social skills

Question 59

What are the phenotypes of ethanol-induced dysmorphology?

Answer 59

FAS, HPE, HPE plus cleft lip

Question 60

Retinoic acid induces _________________

Answer 60

Holoprosencephaly (HPE)

Question 61

Hydrocephaly, microcephaly and increased risk of spontaneous abortions are congenital anomalies caused by ______________

Answer 61

Isotretinoin

Question 62

What were the goals of the iPLEDGE program?

Answer 62

Ensure that no pregnant woman starts taking Isotretinoin and no woman taking Isotretinoin becomes pregnant