TABLE OF CONTENT
SUMMARY……….3
ABBREVIATIONS………..4
1. INTRODUCTION………..5
1.1 Function of the mammary gland………....5
1.2 Cell lineages of the mammary gland………5
1.2.1 Epithelial cells………...6
1.2.2 Stromal cells………...6
1.2.3 Crosstalk between epithelium and stroma……….7
1.3 Mammary gland morphogenesis………8
1.3.1 Embryonic development………8
1.3.2 Pubertal development………...11
1.3.3 Adult homeostasis………...15
1.3.4 Pregnancy, lactation and involution……….16
1.4 Mammary gland stem cells………..19
1.4.1 Transplantation assay to assess the differentiation potential of stem cells………...……….21
1.4.2 Lineage tracing to assess the contribution of stem cells to in vivo tissue development………23
1.5 Aims of the thesis………30
2. RESULTS………..……….32
2.1 Quantitative lineage tracing strategies to resolve multipotency in tissue specific stem cells………..32
2.1.1 Aim of the study………32
2.1.2 Results and methods………..32
2.1.3 Conclusion………34
2.2 ΔNp63 regulates the switch from multipotency to unipotent basal cell fate during embryonic MG development…….………..……….35
2.2.1 Aim of the study………35
2.2.2 Results and methods………..35
2.2.3 Conclusion………37
2.3 Lineage specific ablation induces a switch from unipotency to multipotency in the postnatal mammary gland………..39
2.3.1 Aim of the study………39
2.3.2 Methods………..40
2.3.3 Results……….43
2.3.4 Conclusion………45
3. DISCUSSION……….46
3.1 Quantitative lineage tracing strategies to resolve multipotency in tissue specific stem cells………..46
3.1.1 Inferring cell fate outcome from lineage tracing experiments………46
3.2 ΔNp63 regulates the switch from multipotency to unipotent basal cell fate
during embryonic MG development……….51
3.2.1 Multipotency of embryonic mammary progenitors………51
3.2.2 Transcriptional profiling of the bulk population of EMPs………..52
3.2.3 Single cell transcriptomic analysis………53
3.2.4 Link between embryonic development and cancer………56
3.2.5 Mechanisms of early lineage segregation……….58
3.3 Lineage specific ablation induces a switch from unipotency to multipotency in the postnatal mammary gland………..60
3.4 Further perspectives………65
3.4.1 What is the exact timing of the switch from multipotency to unipotency of EMPs?...65
3.4.2 What are the mechanisms regulating early lineage segregation? Are these conserved in different tissues?...66
3.4.3 Is the reprogramming of adult cells into an embryonic phenotype a hallmark of cancer?...68
3.4.4 How similar are the mechanisms regulating multipotency in different conditions?...69
