molecular patterning during development Flashcards

1
Q

what are 3 principles governing cell differentiation?

A
  • Generative program (The embryo does NOT contain a description of the adult, rather it contains a generative program for making it)
  • Regulatory proteins work together as a “committee” to control the expression of a eukaryotic gene
  • Combinations of a few gene regulatory proteins can generate many different cell types during development
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2
Q

what is the process of cell differentiation?

what does cell differentiation involve?

what does it achieve?

how is it charcterised?

A
  • the process by which embryonic cells become different from one another, which happens very early on soon after fertilisation
  • Involves the emergence of cell types such as muscle, nerve, skin and fat cells
  • Is the achievement of a stable terminal differentiated state (not just transitory differences)
  • Is characterized by the profile of proteins expressed in that cell
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3
Q

list the 3 steps of differentiation from a single fertilised egg to a multipotent stem cell

A
  1. single fertilised egg through cell divisions into morule stage to form totipotent stem cell
  2. then to blastocyst stage, there are two types of cell: placenta cells and the inner cell mass (which becomes the individual) - they are now pluripotent
  3. from pluripotent, they differentiate into different organ systems - they are now multipotent
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4
Q

what is the order of the heirarchy of stem cells?

A

totipotent to pluripotent to multipotent

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5
Q

define potency

A

potency - the entire repertoire of cell types a particular cell can give rise to in all environments

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6
Q

totipotent - define toti

pluripotent - define pluri

multipotent - define multi

A
  • Totipotent: ‘toti’ = whole. eg. Cells of the very early mammalian embryo;
    identical and unrestricted; can give rise to any cell of the body (EMBRYONIC)
  • Pluripotent: ‘pluri’ = more. eg. Inner cells of the blastocyst; less potent;
    can give rise to many cell types but not all (EMBRYONIC)
  • Multipotent: ‘multi’ = many. e.g. Blood stem cells;
    they give rise to cells that have a particular function (ADULT)
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7
Q

cells are committed - this step is a decision that restricts cell fate. what are the 2 stages of commitment?

A

First stage: specification (reversible)
1. Capable of differentiating autonomously if placed in isolation BUT can be respecified if exposed to certain chemicals/ signals.

Second stage: determination (irreversible change)
2. Cell will differentiate autonomously even when exposed to other factors or placed in a different part of the embryo.

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8
Q

in what 2 ways does a naive cell (totipotent) become specified (differentiated)?

A
  • Intrinsic signal – cell autonomous signal tells the cell ‘who is it’
  • Extrinsic signal - a chemical or molecule in the
    environment gives the cell spatial information, tells the
    cell ‘where it is’
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9
Q

what does determination imply?

A

Determination implies a stable change - the fate of determined cells does not change

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10
Q

describe the progress of a cell during development?

what is competence?

A
  1. cytoplasmic determinants or induction
  2. loss of competence* for alternative fates
  3. cell specific gene expression

competence - the ability of a cell to respond to the chemical stimuli (a cell can lose competence by changes in surface receptor or intracellular molecules)

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11
Q

what do patterns in chromatin determine?

what is this called?

describe this mechanism:

A

patterns in chromatin determine the determination of differentiation

this is known a Bivalent chromatin - mechanism basis for these fate decisions

  • only occurs in developmental master regulator genes
  • bivalent chromatin occurs in the promoters of these genes
  • it is a pattern of either open/closed chromatin structure (chemical change of histone proteins)
  • early on the genes are poised - still need to make the decision to be expressed or not^
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12
Q

a combination of a few regulatory proteins can generate many cell types:

where are these proteins acting within the cell?

what are the 2 factors which these sites bind onto?

A

where are these proteins acting within the cell:
- the promoter region
- these regulatory genes are transcription factors used to direct gene expression

note that most of the sites can bind either a stimulatory transcription or inhibitory factor but not both at once. thus the balance of stimulatory and inhibitory transcription factors in a cell determine how strongly it is expressed:

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13
Q

describe endochondrial ossification

A
  • bones form as an early event
  • bones are formed by forming mesochyme
  • which eventually becomes hard bone with chondrocytes and osteoblasts
  • ossification occurs at growth plates
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14
Q

describe intermembranous ossification

A
  • Intramembraneous ossification is the formation of bone in fibrous connective tissue (which is formed from condensed mesenchyme cells)
  • The process occurs during the formation of flat bones such as the mandible and flat bones of the skull
  • the mesoderm is one of the early embryonic germ layers
  • mesenchyme generalised embryonic connective tissue derived from mesoderm
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15
Q

what 2 things do HOX genes determine?

where are they expressed?

A

HOX genes determine the body axis + the position of limbs across it as well as the shape of bones

HOX genes are a related group of genes that are expressed along the long axis of the embryo from head to tail.

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16
Q

During embryonic development HOX genes determine the body axis and the position of the limbs along the body axis - Intrinsic factors

what are the products of HOX genes?

what 3 axes is limb growth regulated?

A
  • The products of HOX genes belong to a class of proteins known as transcription factors, which bind to DNA, and thereby regulate the transcription of other genes (e.g. TBX5, TBX4).
  • Once the cranio-caudal position is set, limb growth is regulated along three axes:
    1. Proximo-distal axis
    2. Antero-posterior axis
    3. Dorso-ventral axis
17
Q

when do upper limb buds appear and where?

when do lower limb buds appear and where?

A
  • Upper Limb buds appear on approximately day 24 between somites C5-T1
  • Lower limb buds appear on approximately day 28 between somites L1-S2
    • By week 8 all major components of the limbs are present
    • Medial rotation of the LL is complete
18
Q

rotation of the limbs:

when do limbs rotate and in which directions and by how much?

where do the flexor compartments lie in upper limb and lower limb?

A
  • Development of fore and hind limbs is similar:
  • In week 7 the forelimbs rotate 90° laterally and the hind limbs rotate 90 ° medially.
  • Results in the flexor compartments being anterior in the upper limb and posterior in the lower limb
19
Q

describe the descriptive terms used in embryology growth

A
20
Q

proximo-distal development (wrist to fingers)

what is proximo-distal development controlled by?

what 2 things does a limb bud consist of?

A
  • controlled by Apical Ectodermal Ridge AER
  • limb bud consists of :
    • core of mesenchyme derived from parietal layer of lateral plate mesoderm
    • ectoderm which forms the outer covering of the limb (epidermis)
      ectoderm is thickened at the ‘apex’ of the developing limb to form the Apical ectodermal ridge
21
Q

what does the AER do in limb development (proximo-distal development)

A
  1. it induces the underlying tissue to remain as a population of undifferentiated mesochymal, rapidly proliferating cells- known as the PROGRESS ZONE
  2. As cells move further away from the AER they will begin to differentiate into cartilage and muscle
  3. This differentiation results in proximo-distal development
22
Q

what are 4 controllers within Proximo-distal development?

A
  1. HOX-8 controls the position of the limb on the long axis of the body
  2. Initiation of outgrowth of the fore limb is controlled by the TBX5 gene and FGF-10
  3. AER secretes FGF4 and FGF8 to maintain the progress zone and the further development of the proximodistal axis
  4. As growth progresses, mesenchymal cells are left behind the advancing ridge (and its influence) and so they begin to differentiate
23
Q

what is the development of the antero-posterior axis (cranio-caudal axis) (thumb to little thinger) controlled by?

what does it ensure?

what does ZPA express?

A
  • controlled by ZPA (zone of polarizing Activity)
  • cluster of cells near the posterior border of the limb form the ZPA which regulated the AP axis
  • it ensures that the thumb grows on the cranial (anterior) side of the limb bud
  • ZPA expresses the protein sonic hedgehog (SHH). ZPA moves distally with the AER
24
Q

how is the dorsal-ventral axis (from back to front) formed?

A
  • BMPs in the ventral ectoderm induce EN1
  • EN1 represses WNT7 restricting its expression to the dorsal limb ectoderm
  • WNT7 induces LMX1 which then specifies the cells to be dorsal
25
Q

how do HOX genes determine the shape of bones?

how are upper limb bones and lower limb bones different?

what is the expression of the HOX genes dependent on?

A

Variations in the combinations of HOX genes ensure that the:

  • Upper and lower limbs are different TBX5 (upper limb), TBX4 (lower limb)
  • Patterns for the proximal (arm) middle (radius and ulna) and distal (hand) are defined

Expression of the HOX genes is dependent on SHH, FGFs and WNT7a

26
Q

in limb development, what is in charge of the shape?

A

apoptosis

27
Q

define:
- amelia
- meromelia
- phocomelia
- micromelia

A
  • Amelia: complete absence of the limbs
  • Meromelia: partial absence of the limbs
  • Phocomelia: absence of long bones
  • Micromelia: segments are abnormally short
28
Q

thalidomide:

how did thalidomide cause an increase in limb abnormalities?

what were the babies which were born associated with?

what did the thalidomide cause?

A

thalidomide was prescribed as a sleeping pill and due to this, there was an increase in incidence of limb abnormalities

12,000 babies survived with phocomelia (flipper like limbs) associated with intestinal atresia and cardiac abnormalities (Hot oram syndrom)

thalidomide caused:
amelia: prolonged or early exposure - leading to total loss of vessels, widespread cell death and all signalling lost

phocomelia: short exposure - leading to loss of blood vessels, uniform or localised cell death, loss or partial loss of ZPA and AER signalling which later recovers to distalise remaining tissue

29
Q

what is hot oram syndrome caused by?

list 4 limb deformities

A
  • TBX5 mutations lead to defects in limb development causing upper limb deformities and heart defects:

brachydactyly - short digits

syndactyly - fused digits due to failure of apoptosis

polydactyly - extra digits

cleft foot - lobster claw deformity