在這個研究中，我們試著去瞭解兩個與Notch相關基因(mib與nicastrin)在斑馬魚早期發育中所扮演的角色。在mib的研究中，我們採用mibnn2002來作為研究材料。因為它具有過去mib突變種所沒有的特殊性狀。這樣的性狀讓我們有機會瞭解mib未知的功能。然而，我們發現這個突變種有一個9.6 Mbp大小的基因片段缺失，其中包含了foxc1a與mib基因。mib基因的遺失導致其呈現與mibtfi91相似的分子性狀，包含her4表現量下降、神經元細胞些微增加以及冷敏感性的dlc同步表現異常。雖然在這個研究中，我們沒有藉由研究此突變種的特殊性狀找到mib的新功能，我們卻發現了foxc1a只在早期肌節特化上是必要的，較晚生成的肌節則不用，這點發現修正了早先對foxc1a在肌節特化上功能上的結論(過去認為foxc1a基因是早期跟晚期的肌節發育皆必要的基因)。這個發現也與新近由foxc1a變異種研究所得的結論吻合，該研究發現foxc1a基因是早期的肌節發育所必需的。而在nicastrin的研究中，我們發現在胚胎黑色素細胞中，γ-secretase需要Nicastrin來執行它的功能。當nicastrin的mRNA缺乏時，會導致黑色素細胞死亡，視網膜色素上皮退化與視覺感光細胞退化。我們發現黑色素小體在黑色素細胞中的成熟需要nicastrin。 我們猜測不成熟的黑色素小體中的Tyrosinase下游產物，可能會導致我們觀察到的粒線體結構異常與黑色素細胞壞死。利用藥物抑制Tyrosinase，其結果也支持這樣的想法。除了黑色素細胞外，我們也發現自由基抑制藥物，在存在視網膜色素上皮的情況下，可以在一定程度上緩解視覺感光細胞在nicastrin突變種中的退化現象。簡要來說，我們發現foxc1a的表現是mibnn2002突變種早期的肌節特化需要的，但其表現與否並不影響mibnn2002突變種晚期的肌節特化；黑色素細胞中的黑色素小體成熟需要nicastrin的表現。缺乏nicastrin會導致黑色素細胞產生Tyrosinase介導的粒線體腫脹與黑色素細胞壞死。

Here, we examined the function of two Notch related genes, mib and nicastrin, in zebrafish early development. In the study of mib, its function was studied by the mibnn2002 mutant, which showed distinct phenotypes from previous mib mutants and might reveal novel function of mib. However, a 9.6 Mbp chromosome deletion was found in mibnn2002, which includes foxc1a and mib. The deletion of mib results in the down-regulation of her4, neuronal cell slighly increase and cold sensitive dlc synchronization defect which mimics the molecular phenotypes of mibtfi91. Although we did not identify a new function of mib through studying its distinct phenotypes, we found that foxc1a is only required for the specification of early somites, but not later somites. The finding rectifies previous conclusion, which suggests that foxc1a is required for not only early somitogenesis but also late somitogenesis. This finding is also echoed by a recent report, which showed that foxc1a is required for early somitogenesis. In the study of nicastrin, we found that Nicastrin is required for the function of γ-secretase in the embryonic melanocytes. The deficiency of nicastrin transcript could lead to depigmentation, retinal pigment epithelium degeneration and photoreceptor degeneration. nicastrin was found to be required for the maturation of melanosomes in the melanocytes. Mitochondria malformation and melanocyte necrosis were suppressed by the treatment of Tyrosinase inhibitor. In contrast to melanocytes, ROS inhibitor, in addition to the existence of RPE, was required to partially rescue the photoreceptors in the nicastrin mutant. In short, we found that the expression of foxc1a in the PSM is only required for early somite specification, but not late somite specification in the mibnn2002 mutant; The expression of nicastrin is required for melanosome maturation in the melanocytes. The deficient of nicastrin transcript in the melanocyte could lead to Tyrosinase mediated mitochondria swelling and cell necrosis.

List of Figures............................................................................................................3
List of abbreviations..................................................................................................5
CHAPTER I: Introduction.........................................................................................7
1.1. Zebrafish.........................................................................................................7
1.2. Notch..............................................................................................................8
1.3. Mind bomb (Mib) and somite.......................................................................10
1.4. Somite formation..........................................................................................11
1.5. Nicastrin, γ-secretase and melanocytes........................................................13
1.6. Depigmentation and its potential mechanisms.............................................15
1.7. Study new function of Mib and functions of nicastrin in zebrafish early
development.................................................................................................17
CHAPTER II: Materials and Methods - mib nn2002 ....................................................19
2.1 Zebrafish........................................................................................................19
2.2 foxc1a rescue and tp53 knockdown experiments..........................................20
2.3 Whole mount in situ hybridization (WISH)..................................................20
2.4 Tunel and Acridine Orange staining..............................................................21
2.5 γ-H2AX staining............................................................................................21
2.6 Genomic PCR and RT-PCR...........................................................................22
2.7 RNA preparation for Illumina RNA-seq.......................................................22
CHAPTER III: Results-mib nn2002 ..............................................................................23
3.1 mib nn2002 showed similar Notch molecular phenotypes, but distinct
morphological phenotypes.............................................................................23
3.2 mib nn2002 mutants showed defects in somite formation without disrupting
Notch signaling in the PSM...........................................................................29
3.3 mib nn2002 showed a specification defect in the anterior somites.....................32
3.4 foxc1a is not essential for later somite specification and boundary formation
.................................................................................................................39
3.5 mib nn2002 showed tp53 up-regulation and an increase of apoptosis since 17
hpf .................................................................................................................41
3.6 mib gene is deleted in mib nn2002 mutants.........................................................45
3.7 mib nn2002 is a chromosome arm deleted mutant, which includes the loci of
mib and foxc1a...............................................................................................47
3.8 The early somite specification defect can be partially rescued by foxc1a
overexpression, while the apoptosis was partially reduced by tp53
knockdown....................................................................................................55
CHAPTER IV: Discussion-mib nn2002 ........................................................................60
4.1 mib nn2002 mutant is a chromosome-deleted mutant, including mib and foxc1a
......................................................................................................................60
4.2 The deletion could be a result of ENU mutagenesis.....................................60
4.3 Chromosome truncated mutant could be a powerful tool in assisting genome
assembly........................................................................................................61
4.4 foxc1a could only be required for early somites' specification, but not the
late ones.........................................................................................................62
4.5 The function of Mib in the mib nn2002 and mib tfi91 may be complemented by the
function of Mib2 in the PSM.........................................................................62
4.6 The deleted genes in the mib nn2002 mutant could be essential in maintaining
genome stability.............................................................................................63
CHAPTER V: Methodology-nicastrin hi1384 ..............................................................65
5.1 Zebrafish........................................................................................................65
5.2 Genomic PCR and RT-PCR...........................................................................65
5.3 Live and WISH imaging................................................................................66
5.4 PCR-based chromosome walk.......................................................................66
5.5 Whole mount in situ hybridization................................................................66
5.6 nicastrin knockdown and mRNA rescue experiments..................................67
5.7 Section and Hematoxylin & Eosin staining...................................................67
5.8 Transmission electron microscope image......................................................68
5.9 Drug treatments.............................................................................................68
5.10 Statistics.......................................................................................................69
CHAPTER VI: Results-nicastrin hi1384 ......................................................................70
6.1 nicastrin hi1384 homozygotes showed hypopigmentation and curly up tail
phenotypes.....................................................................................................70
6.2 GT2.0 virus insertion in the Intron 1 of nicastrin gene could lead to the
down-regulation of nicastrin mRNA in the nicastrin hi1384 mutants...............72
6.3 nicastrin hi1384 mutants showed depigmentation phenotype instead of
hypopigmentation..........................................................................................74
6.4 nicastrin hi1384 mutants showed retinal pigment epithelium and photoreceptor
degeneration..................................................................................................80
6.5 Depigment and curly up tail phenotypes in nicastrin hi1384 mutants can be
rescued by injecting nicastrin mRNA...........................................................84
6.6 A defect in melanosome maturation could lead to melanocyte necrosis in the
nicastrin hi1384 mutants.....................................................................................88
6.7 The necrosis in the nicastrin hi1384 mutant could be a result of mitochondria
damage...........................................................................................................95
6.8 The depigmentation phenotypes in the nicastrin hi1384 were
Tyrosinasedependent..............................................................................................99
6.9 Down-regulating γ-secretase activity also induced Tyrosinase dependent
depigmentation in the embryonic melanocytes...........................................106
6.10 In addition to Tyrosinase inhibitor, anti-oxidant is also required to protect
the photoreceptors in the nicastrin hi1384 mutants.........................................112
CHAPTER VII: Discussion-nicastrin hi1384 .............................................................115
7.1 nicastrin hi1384 mutants showed Tyrosinase dependent mitochondria damage
and cell death through impairing melanosome maturation.........................115
7.2 nicastrin was only temporarily required to prevent the curly up tail
phenotype.....................................................................................................117
7.3 nicastrin transcript down-regulation could be a result of trans-activation
defect...........................................................................................................118
7.4 Nicastrin is required for the function of γ-secretase in the melanocytes.....118
7.5 The down-regulation of γ-secretase's activity could lead to melanosome
immaturation, mitochondria swelling and necrosis.....................................119
7.6 nicastrin deficiency triggers photoreceptor ROS stress via an unknown
mechanism...................................................................................................120
7.7 nicastrin hi1384 mutant is a new Vitiligo disease model..................................121
7.8 Peventive Tyrosinase inhibitor administration could be a potential strategy in
vitiligo prevention.......................................................................................123
7.9 Down-regulating γ-secretase activity and raising Tyrosinase activity is a
potential treatment for patients suffered with melanoma............................124
7.10 The potential association of nicastrin and photoreceptor degeneration....125
Appendix I: The primers for mib nn2002 ....................................................................126
Appendix II: The truncated region in the mib nn2002 ................................................127
Appendix III: The offsprings of nicastrin hi1384 .......................................................128
Appendix IV: RT-PCR Primers used in nicastrin hi1384 ...........................................129
Appendix V: DAPT is able to induce somite boundary formation defect.............130
References.............................................................................................................132

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