Cell proliferation & differentiation

1. 1
Cell Proliferation & Differentiation
in Embryo Development
Department of Histology & Embryology
Ling xiao

2. •During embryonic development, a fertilized
egg gives rise to many different cell types
A Genetic Program for Embryonic
Development

3. 3
•During embryonic development, a fertilized egg gives
rise to many different cell types
•Cell types are organized into tissues, organs, organ
systems, and the whole organism
•Gene expression controls this development
•The transformation from zygote to adult results from
cell proliferation,cell differentiation,and
morphogenesis.
A Genetic Program for Embryonic
Development

4. 4
What is cell proliferation?
•Cell proliferation is a process of cell
division and regeneration, which
results in an increase in the cell
number with exact passages of
genetic information to their daughter
cells.

5. 5
Proliferation
of eukaryotic
cell
DNA replication
What is cell cycle?
•Cell cycle is defined as a period from
the end of one division to the
beginning of next division of a
proliferative cell.

6. 6
Phases of the cell cycle
G1 phase
S phase
G2 phase
M phase

7. 7
Phase of cell cycle
•M-Phase
–Mitosis
–Cytokinesis
•Interphase
–G1 = Gap between M and S
–S = Synthesis (DNA and
centrosomes replicated)
–G2 = Gap between S and M

8. 8
Cell Cycle Regulation
•Cyclins
•Cyclin Dependent Kinases (CDKs)
•Cyclin Dependent Kinases Inhibitors (CDKIS)

9. 9
The Nobel Prize in Physiology or Medicine 2001 was awarded jointly
to Leland H. Hartwell, Tim Hunt and Sir Paul M. Nurse "for their
discoveries of key regulators of the cell cycle".
Leland H. Hartwell Tim Hunt Sir Paul M. Nurse

10. 10
For adult
•Cycling cellswith continuous division
Embryo cells, hematopoietic cells
•Differentiated cells
Cardiac cells, nerve cells
•Most cells
Skin fibroblasts, SMCs, VECs, cells of
internal organs

11. 11
For Embryo

12. 12
For Embryo

13. 13
For Embryo

14. 14
For Embryo
•Cleavage is a series of rapid cell divisions without
cell growth or gene expression which occurs in
early embryogenesis.
•Early cleavage divisions in most embryos are
reductive. During cleavage, the cytoplasm is
divided into smaller and smaller cells, called
blastomeres. The total cellular volume of the
embryo stays the same, but the number of cells
within the embryo increases.
•Cleaving cells have a modified cell cycle, in which
the two gap phases, G1 and G2, are completely
omitted. The cells cycle rapidly between M and S
phases.

15. For Embryo
•Cleaving cells have
a modified cell cycle,
in which the two gap
phases, G1 and G2,
are completely
omitted. The cells
cycle rapidly
between M and S
phases.
15

16. 16
For Embryo
•Morula stage(16-cell stage):
Compaction
Polarity

17. 17
Stages of mouse and human preimplantation development.
(TE: trophectoderm; ICM: inner cell mass ; EPI: epiblast;
PE: primitive endoderm)

18. 18

19. 19
Cockburn K, Rossant J. Making the blastocyst: lessons
from the mouse. J Clin Invest. 2010, 120(4): 995-1003.

20. 20
Abnormal Cleavage
•Delay of cleavage: implantation failure
•Irregular cleavage: abnormal zygote
•Polyspermous fertilization: Polyploid
•Enzygotic twins

21. 21

22. 22
Siamese twins

23. 23
Control of early embryo development
•Before genome activation
Maternal-effect genes (miRNAs,
transcriptional factors, DNA
methyltransferase, …)
•After genome activation
Transcriptional factors (Cdx2, Oct4…)
Heat shock proteins
Cytokines…

24. 24
Cdx2
Oct4

25. 25

26. 26
When a cell divides by mitosis it
produces two “daughter cells”
with identical sets of chromosomes.
SO, HOW DO THESE CELLS
BECOME DIFFERENT FROM ONE
ANOTHER?

27. 27
What is cell differentiation?
•Cell differentiation is a cellular
events that gives rise to different
kinds of cells with the specialized
morphology, metabolism and
physiological functions from the cells
of the same origin.

28. 28
What is cell differentiation?

29. 29
•Determination commits a cell to its final fate.
•Determination precedes differentiation.
•Cell differentiation is marked by the production
of tissue-specific proteins.
Cell Determination &
Differentiation

30. 30
Cytoplasmic Determinants and
Inductive Signals
•An egg’s cytoplasm contains RNA, proteins, and other
substances that are distributed unevenly in the
unfertilized egg.
•Cytoplasmic determinants are maternal substances in
the egg that influence early development.
•As the zygote divides by mitosis, cells contain different
cytoplasmic determinants, which lead to different gene
expression.

31. 31(a) Cytoplasmic determinants in the egg
Two different
cytoplasmic
determinants
Unfertilized egg cell
Sperm
Nucleus

32. 32(a) Cytoplasmic determinants in the egg
Two different
cytoplasmic
determinants
Unfertilized egg cell
Sperm
Fertilization
Zygote
Nucleus

33. 33(a) Cytoplasmic determinants in the egg
Two different
cytoplasmic
determinants
Unfertilized egg cell
Sperm
Fertilization
Zygote
Mitotic
cell division
Two-celled
embryo
Nucleus

34. 34(b) Induction by nearby cells
Signal
molecule
(inducer)
Signal
transduction
pathway
Early embryo
(32 cells)
NUCLEUS
Signal
receptor

35. 35
Totipotent Pluripotent Unipotent DifferentiatedTotipotent Pluripotent Unipotent DifferentiatedTotipotent →Pluripotent→ Unipotent →Differentiated

36. 36
Control of Cell Differentiation
–Gene control
–Cell interaction
–Hormones
–Environmental factors

37. 37
Gene control
•Housekeeping Genes serve a function
required in all the cell types of an organism,
regardless of their specialized role. (Helper)
•Luxury genes perform specialized function
in a definite type of cell, not required by all
cell types of an organism. (Determinant)

38. 38

39. 39
Example
•Myoblastsproduce muscle-specific proteins and form
skeletal muscle cells
•MyoDis one of several “master regulatory genes” that
produce proteins that commit the cell to becoming
skeletal muscle
•The MyoD protein is a transcription factorthat binds to
enhancersof various target genes

40. 40
Embryonic
precursor cell
Nucleus
OFF
DNA
Master regulatory gene myoD Other muscle-specific genes
OFF

41. 41
Embryonic
precursor cell
Nucleus
OFF
DNA
Master regulatory gene myoD Other muscle-specific genes
OFF
OFFmRNA
MyoD protein
(transcription
factor)
Myoblast
(determined)

42. 42
Embryonic
precursor cell
Nucleus
OFF
DNA
Master regulatory gene myoD Other muscle-specific genes
OFF
OFFmRNA
MyoD protein
(transcription
factor)
Myoblast
(determined)
mRNA mRNA
Part of a muscle fiber
(fully differentiated cell)
MyoD

43. 43
Embryonic
precursor cell
Nucleus
OFF
DNA
Master regulatory gene myoD Other muscle-specific genes
OFF
OFFmRNA
MyoD protein
(transcription
factor)
Myoblast
(determined)
mRNA mRNA mRNA mRNA
Myosin, other
muscle proteins,
and cell cycle–
blocking proteins
Part of a muscle fiber
(fully differentiated cell)
MyoD Another
transcription
factor

44. 44
Cell interaction
•Cell induction
•Contact inhibition
•Microenvironment--extracellular
matrix

45. 45
Cell induction
•Induction is the process by which one group
of cells produces a signal that determines
the fate of a second group of cells.

46. 46
Example

47. 47
Extracellular matrix (ECM)
•ECM can control the differentiation by
influencing the intracellular gene
expressions via signal transduction.

48. Exogenous ECM prevents the inhibition of skeletal muscle
differentiation by proteoglycan synthesis inhibitors.
Osses N , and Brandan E Am J Physiol Cell Physiol 2002;282:C383-C394
Chlorate and BDX
can inhibit the
proteoglycan
synthesis.

49. 49
Hormones
•Steroids
•Peptides
To influence the gene expressions through
binding with the corresponding receptors
Target cells

50. 50
Environmental factors
1) Biological
Viruses:
–rubella virus→ cataracts, deafness, cardiac
defects;
–cytomegalovirus→ blindness, microcephaly,
hepatosplenomegaly;

51. 51
2)Physical
radiation,mechanicalpressure,trauma
Radiation:WorldWarII:atomicbomb
explosionoverJapan.
Survivedpregnantwomen:
28%aborted;
25%deliveredchildrendied<1year;
25%infantswithCNSmalformations.

52. 52
3)Chemical
chemicals:nitrite,mercury,lead,etc.
drugs:thalidomide(ameliaandmeromelia)

53. 53
4)Others
hypoxia
nutritionaldeficiencies
…………

54. 54
Susceptibleperiod
1)Dependentonthedevelopmentalstage.
Theembryonicperiod(3-8weeks)is
thehighestsusceptibleperiod.

55. 55
2) Different organs have different susceptible period
corresponding to their own critical development stage.

56. 56
Summary
Embryo development: From one single
zygote to a complex human body
Cell proliferation: Increase of cell numbers
(cleavage)
Cell differentiation: Formation of different
cell types (cell determination)
Control factors: gene, cell communication,
ECM, hormone, environmental factors