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Flashcards in Homeobox Genes Deck (87):
1

The important question of "how do we develop our body plan" has been extensively studied in which two model organisms?

Drosophila Melanogaster (fruit fly) and Mus musculus (house moue)

2

One advantage of using the fruit fly is that they have a short generation time. How long does it take for the fruit fly to go from egg to adult?

14 days

3

One advantage of using the mouse is that they are very amenable to genetic manipulations such as

Gen knockouts and knock ins, and transgenics

4

Deleting a gene via embryonic stem (ES) cells

Gene knockout

5

Replacing one version of a gene with another via embryonic stem cells

Gene knockin

6

Adding extra copis of any gene

Transgenics

7

In early mouse development, the group of cells in the center of the blastocyst is called the

Inner cell mass (ICM)

8

Pluripotent for the embryo

ICM cells

9

Cells in the outer epithelium are committed to generate part of the

Placenta

10

Can be isolated and grown in cultures

ICM cells

11

These mice ICM cells retain their pluripotency in vitro and are called

Embryonic stem (ES) cells

12

Enable a mouse to be generated that has a specific DNA change that we want to study

The pluripotent ES cells

13

If you delete a gene in the ES cells then a mouse can be generated that contains all the genes in the genome except the specific one that was deleted. These mice are called

Kock-outs

14

If you introduce more subtle specific changes into the DNA such as replacing a wild type sequence with a specific mutation, then you get mice called

Knock-ins

15

The insertion of DNA into the genome. DNA is not deleted, rather, extra copies of a gene are added. Mice that undergo this process are called

Transgenics

16

How are transgenics made?

DNA injected into nuclei of fertilized egg

17

Mutations where one structure is replaced with another or is duplicated

Homeotic Mutations

18

Homeotic mutations were known to exist since the 1930's, but the genes responsible for these defects were not known until the development of

DNA recombinant technology (1980's)

19

Cloning of genes responsible for homeotic mutations was first achieved in

Drosophila

20

Sequence homology was observed between genes responsible for different homeotic mutations. This DNA sequence was termed the

Homeobox

21

The homeobox is 180 bp in length and encodes a protein called a homeobox transcription factor. The part of the protein that binds DNA is called the

Homeodomain

22

Encode transcription factors that typically initiate a cascade of gene expression necessary for the development of a body structure or cell type

Homeobox genes

23

Homeobox proteins are transcription factors that bind DNA in a sequence specific manner. All homeobox proteins bind

AT rich elements in promoters and enhancers

24

The homeodomain amino acid sequence is responsible for binding and recognizing the AT rich binding site found in many

Promoters and Enhancers

25

The homeodomain protein sequence is comprised of 3 alpha helices. Which helix makes direct contact with the DNA?

The 3rd helix

26

All homeobox transcription factors bind

AT rich DNA sequences

27

In vitro, homeobox proteins demonstrate little or no specificity. However, in vivo, homeodomain transcription factors form protein complexes to determine

Specificity (very important in vivo or legs would be arms)

28

Only makes up a small portion of the homeobox transcription factor

Homeodomian

29

Other proteins bind to different parts of homeobox transcription factors to modify function and help determine

Specificity

30

There are many genes that contain homeobox sequences. These genes are broken into which two classes?

1.) Hox genes
2.) Genes that when mutated, do not result in structural change

31

Genes that when mutated result in homeotic transformations

Hox Genes

32

The second class of homeobox sequences are not physically

Clustered together

33

Control the patterning of cell types, and mutations in these genes often result in the loss or gain of parts of cell types

Second class genes

34

Clustered into 4 physically linked groups in humans

Hox genes

35

In the evolution from drosophilia to mouse to human, there is a consistent increase in the number of

Homeobox genes (i.e. from 1 to 4)

36

Function in patterning the body axis

Hox genes

37

Expressed in specific embryonic domains and function in the generation of that particular body part

Hox genes

38

Hox genes are positioned on the chromosome in the same order in which they are expressed. Where are the following genes expressed?
1.) Genes positioned 5' in the Hox cluster
2.) Genes positioned 3' in the Hox cluster

1.) Posterior domain
2.) Anterior domain

39

How many Hox clusters are present in mice and humans?

4 (Hox a, b, c, and d)

40

Homologous genes between species

Orthologs

41

Homologous genes within a species

Paralogs

42

Expressed in the developing neural tube as well as the flanking somites

Mouse Hox genes

43

Body segments containing the same internal structures

-seen in embryonic mouse

Somites

44

Somite expression is always shifted

Posteriorly

45

Hox genes further 3' have more anterior expression boundaries. This is called

Spacial co-linearity

46

3' Hox genes are also expressed earlier in development than 5' genes. This is called

Temporal co-linearity

47

Different groups of cells express distinct patterns of Hox genes depending on their position along the anterior-posterior (A-P) axis. This is called the

Hox code

48

Dictates the development of different structures along the A-P axis

Hox code

49

Hox genes are transcription factors, so they will determine which downstream genes get turned

On

50

These downstream genes will in turn determine the developmental structures that will be

Derived

51

Loss of function Hox mutations (knock-outs) lead to

Anterior transformations

52

Gain of function Hox mutations lead to

Posterior transformations

53

Have less severe phenotype than double or triple mutants

-an example of redundancy or overlapping function

Single mutants

54

Function as transcription factors so they either initiate or repress downstream gene expression

Hox genes

55

One function of Hoxa2 and Hoxb2 is to initiate gene expression responsible for the generation of

Cervical vertebrae C2

56

Hoxa3, Hoxb3 and Hoxd3 are expressed in a more posterior compartment and one of their functions is to initiate gene expression responsible for the generation of

Cervical vertebrae C3

57

Hoxa2, Hoxb2, Hoxa3, Hoxb3 and Hoxd3 are all co-expressed in the same set of cells along the A-P axis. What would happen if a deletion knocked out Hoxa3, b3, and d3?

A second C2 vertebrea would form instead of a C3

58

Initiates the expression of genes responsible for the generation of C4 vertebrae

Hoxd4

59

Every Hox gene works together with the Hox genes located

Downstream in the cluster

60

In a transgenic mouse with misexpression of Hoxd in a more anterior structure, we would see

2 C4 vertebrae and no C3

61

Hox gene expression extends as far anterior as the

Hindbrain

62

Formation of Drosophila head structures is controlled by a homeobox transcription factor called

-NOT part of the Hox cluster

Orthodenticle (Otd)

63

No hox genes are expressed in the

Anterior head structures

64

Mice and humans have 2 Otd analogs called

Otx1 and Otx2

65

Drosophila Otd is expressed in anterior blastocyst in a region of the embryo that will give rise to

Anterior brain structures

66

Drosophila null mutants for Otd result in embryos without

Head and brain structures

67

Mice with Otx1 knockouts survive embryogenesis, but have

Smaller brains

68

Results in lethality and the deletion of forebrain structures during early mouse development, which is similar to the Otd Drosophila phenotype

Otx2 knockout

69

These studies demonstrate that Otx or Otd transcription factors are essential for regulating gene expression necessary to generate

Anterior (head/forebrain) brain structures

70

Turn on a series of downstream genes, which then function together to generate head/forebrain structures

Otc and Otx1/2

71

Situated at the top of a transcriptional cascade and NO other transcription factor in the genome is capable of performing this function

Otd and Otx1/2

72

Overexpression of Otd or Otx results in a

Larger brain

73

When mouse Otx1 was expressed in drosophila in place of Otd, the result was

Larger brains (shows functional redundancy)

74

What hapened when fly Otd was inserted into a mouse in place of Otx1?

The brain size was equal to wild type

75

Fly Otd is functionally equivalent to

Mouse Otx1

76

Caused by diseases such as amyotrophic lateral sclerosis (ALS), spinal muscular atrophy, progressive muscular atrophy or by injury to the spinal cord

Motor neuron damage

77

Can generate mature cell types in vitro

ES cells

78

Basic science has identified a cascade of transcription factors required for

Motor neuron generation

79

Researchers have used this knowledge to generate motor neurons in culture from

ES cells

80

A transcription factor code has been identified for generating embryonic stem cells. These genes can convert other cell types into ES cells. What are the genes?

OCT4 and NANOG (homeobox TF's), SOX2, C-MYC, and KLF4

81

The forced expression of these genes in skin fibroblasts converts them to

Induced pluripotent stem cells (iPS cells)

82

Have been implicated in human disease

Homeobox genes

83

Important for patterning the vertebrate limbs

Hox genes

84

Mutations in HOXD13 in both humans and mice result in digit malformations known as

Synpolydactyly

85

Observed in individuals with hand malformations

Missense mutations in HOX13D (3rd alpha-helix)

86

Protein modeling studies indicated that these amino acid changes affect the 3-D configuration of the

Hox gene

87

Protein-DNA binding assays demonstrate that the the missense mutations affect

DNA binding

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