Angela A. Garibaldi GS Papers 1

XD Lab Related Papers

1. Dai X and Segre JA. Transcriptional control of epidermal specification and differentiation. Curr Opin Genet Dev. 2004 Oct;14(5):485-91. DOI:10.1016/j.gde.2004.07.002 |
2. Nair M, Teng A, Bilanchone V, Agrawal A, Li B, and Dai X. Ovol1 regulates the growth arrest of embryonic epidermal progenitor cells and represses c-myc transcription. J Cell Biol. 2006 Apr 24;173(2):253-64. DOI:10.1083/jcb.200508196 |
3. Wells J, Lee B, Cai AQ, Karapetyan A, Lee WJ, Rugg E, Sinha S, Nie Q, and Dai X. Ovol2 suppresses cell cycling and terminal differentiation of keratinocytes by directly repressing c-Myc and Notch1. J Biol Chem. 2009 Oct 16;284(42):29125-35. DOI:10.1074/jbc.M109.008847 |
4. Teng A, Nair M, Wells J, Segre JA, and Dai X. Strain-dependent perinatal lethality of Ovol1-deficient mice and identification of Ovol2 as a downstream target of Ovol1 in skin epidermis. Biochim Biophys Acta. 2007 Jan;1772(1):89-95. DOI:10.1016/j.bbadis.2006.08.012 |
5. Sauer B and Henderson N. Site-specific DNA recombination in mammalian cells by the Cre recombinase of bacteriophage P1. Proc Natl Acad Sci U S A. 1988 Jul;85(14):5166-70. DOI:10.1073/pnas.85.14.5166 |

(2004-Review)Transcriptional control of epidermal specification and differentiation

Definitions

1. ectopic - an event occurring at an incorrect or undesirable location. Pertaining to or characterised by ectopia biology-online.org dictionary
2. stratification - use of chemical of mechanical systems to break dormancy and increase germination biology-online.org dictionary
3. epigenetic -is the study of inherited changes in phenotype (appearance) or gene expression caused by mechanisms other than changes in the underlying DNA sequence, hence the name epi- (Greek: επί- over, above) -genetics. These changes may remain through cell divisions for the remainder of the cell's life and may also last for multiple generations. However, there is no change in the underlying DNA sequence of the organism;[1] instead, non-genetic factors cause the organism's genes to behave (or "express themselves") differently.[2] Wikipedia
4. ΔNp63- oncogenic isoform of the p63 protein (homolog to human p53 tumor suppressor gene) Scientific Paper
5. keratinocytes- Keratinocytes are the most common type of skin cells. They make keratin, a protein that provides strength to skin, hair, and nails. Keratinocytes form in the deep, basal cell layer of the skin and gradually migrate upward, becoming squamous cells before reaching the surface of the skin over the course of a month. About.com
6. TAp63 - one of six proteins produced by the p63 gene. It remains intact during cancer, and halts tumor growth by inducing senescence in the tumor cells so that they are still metabolically alive, but cannot divide. Medical News
7. proto-oncogene- A normal gene which, when altered by mutation, becomes an oncogene that can contribute to cancer. Proto-oncogenes may have many different functions in the cell. Some proto-oncogenes provide signals that lead to cell division. Other proto-oncogenes regulate programmed cell death (apoptosis). Medicine Net
8. TA Cells (transit-amplifying)-

Summary

Introduction

• Imbalance in the normal process of differentiation and proliferation can cause skin disorders/cancer.
• Transcription factors integrate/interpret signals from upstream developmental/growth factor signaling pathways in order to execute downstream differentiation/morphogenetic processes.

Stem cell maintenance and proliferation

• Key Regulators of SC (stem cell) maintenance and epidermal proliferation: p63, c-Myc, Gli, Id TFs
• p63 is a homolog of the p53 tumor suppressor in humans and epidermal master regulator

p63

Conflicting Interpretations of Results:
McKeon's - p63 involved in SC maintenance, but not epidermal maturation
Roop's- p63 determining factor of stratification (No early 

or late epidermal differentiation markers expressed in the mutants)

• ΔNp63 maintains the proliferation state, doesn't promote it. (Over-expression experiments)
• TAp63 can drive epidermal specification

c-Myc

• induces proliferation by controlling the G1-S cell cycle transition
• epidermal expression only in proliferating basal cells
• increased expression in keratinocytes promotes terminal differentiation and progressive decrease in growth
• Key regulator of epidermal proliferation by converting StemCells to TransitAmplifying Cells

How?

(2006)Ovol1 Regulates the growth arrest of embryonic progenitor cells and represses c-myc transcription

Definitions

1. progenitor cell- Like stem cells, progenitor cells have a tendency to differentiate into a specific type of cell.[1] In contrast to stem cells, however, they are already far more specific: they are pushed to differentiate into their "target" cell. The most important difference between stem cells and progenitor cells is that stem cells can replicate indefinitely, whereas progenitor cells can only divide a limited number of times. Controversy about the exact definition remains and the concept is still evolving. Wikipedia
2. acanthosis-an abnormal but benign thickening of the prickle-cell layer of the skin (as in psoriasis) freedictionary

Summary

Introduction

• Ovol1 expressed in skin, kidney, male germinal epithelium
  • required to restrict proliferation potential of embryonic progenitor cells
  • represses expression of c-myc by direct binding to its promoter, regulating proliferation arrest of developing epidermal cells.

Results

• Put the Ovol1 mutation on B6 background because it can sometimes enhance the phenotypic manifestation and analyzed skin morphology of the +/- (intercrosses)
  • In the past it was put onto the 129 x B6 (50/50) background
  • Both display the same phenotypes: ruffled hairs, cystic kidneys
  • Some of the Ovol1- pups died immediately before/after birth, the surviving ones had flaky skin.
• Skin morphology
• Figure 1: When comparing the WT and the -/- mutant E15.5 (early stage) - lack of morphological distinction between the suprabasal and basal layers in many areas. More mitotic figures were seen. E16.5

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(2009)Ovol2 Suppresses Cell Cycling and Terminal Differentiation of Keratinocytes by Directly Repressing c-Myc and Notch1

Summary

Results

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