臺灣博碩士論文加值系統

Nolz-1 (Znf503/Zfp503, Mouse Genome Informatics) 為鋅指基因。 Nolz-1 屬於哺乳類nocA/elb/tlp-1 (NET) 家族的一員。我們實驗室先前研究中發現Nolz-1主要功能為轉錄抑制因子於N2A和ST14A神經細胞株。其他研究也指出，斑馬魚和雞的同源Nolz-1基因分別為Nlz1/Nlz2其功能上亦扮演著轉錄抑制作用分別調控著後腦和脊髓的發育。然而我們實驗室同時發現Nolz-1表現於發育中老鼠的中腦腹側區。此論文目的在於觀察及探討Nolz-1對於多巴胺神經元發育過程中的調控。論文的第一部分，利用蛋白質免疫染色和原位雜交觀察Nolz-1在中腦的多巴胺神經細胞的表現。於胚胎第13.5和15.5的老鼠中，Nolz-1主要表現在多巴胺神經元的兩側，其區域為腹側區的多巴胺神經元早期表現之區域。然而於第18.5和出生後第零天的老鼠中，此時期的中腦多巴胺神經元可被分為腹側和黑質兩個子區域，發現 Nolz-1蛋白質和mRNA表現於腹側區，並非黑質區。出生後第7和第14天，Nolz-1蛋白質和mRNA還是持續表現於腹側區。但是Nolz-1蛋白質和mRNA於第七天、第十四天短暫的表現於黑質區。Nolz-1蛋白質和mRNA 並沒有在成熟中腦多巴胺神經元中發現。論文第二部分，探討Nolz-1表現的多巴胺神經元是否會共同表現興奮性神經傳導物質-麩胺酸或是抑制性神經傳導物質-γ-胺基丁酸，並探討Nolz-1表現之多巴胺神經元的下游投射核區。首先透過免疫染色Nolz-1和酪氨酸羥化酶(TH)和原位雜交vGlut2的方法，發現Nolz-1表現的多巴胺神經元會表現較低量的vGlut2 mRNA。另一方面，利用GAD2-Cre;Ai14的老鼠來代表-γ-胺基丁酸神經元（此老鼠的腦中表現tdTomato同時亦為γ-胺基丁酸神經元），發現Nolz-1表現的多巴胺神經元不會表現於-γ-胺基丁酸神經元中。最後利用逆行突觸追蹤劑打入出生後兩天老鼠的腦中且於第七天犧牲切片染色，逆行突觸追蹤計分別打入老鼠中腦腹側區的下遊核區:內側前額葉皮質區、隔膜區、杏仁核和伏隔核。發現腹側區的Nolz-1表現之多巴胺神經元主要投射至內側前額葉皮質區和隔膜區，而只有少量細胞會投射至杏仁核和伏隔核。論文的第三部分，重點在於分子機制上的的探討。我們利用增加和剔除Nolz-1表現的方法。首先利用Nestin-cre將Nolz-1異位表現於神經細胞。腹側區多巴胺表現Otx2（腹側區的表徵）上升，然而腹側區多巴胺表現Sox6（黑質區的表徵）下降。此結果可知增加Nolz-1可能會促進腹側區的多巴胺神經元的型態。然而在增加Nolz-1的表現並不會改變黑質區多巴胺神經元表現Otx2和Sox6。接下來利用DAT-Cre mice，專一性的增加Nolz-1表現於多巴胺神經元。在腹側區多巴胺表現Otx2在第5個切面中增加，但Sox6並不會被改變，然而卻對黑質區calbindin的表現在第5個切面中有趨勢的增加（另一個腹側區的表徵）。另一方面也觀察到黑質區的Sox6 的表現下降於第1個切面，卻不會改變Otx2的表現。這些結果顯示出增加Nolz-1的表現在腹側區會增強腹側區多巴胺的表徵，然而異位表現Nolz-1在黑質區可能誘導黑質區的細胞變成腹側區多巴胺神經細胞。另一方面，同時也利用DAT-Cre mice，專一性的剔除Nolz-1表現於多巴胺神經元。Nolz-1剔除後使得Otx2的表現於腹側區下降，同時卻使得Sox6、Satb1、以及Girk2（均為黑質區的表徵）的表現上升。相反的專一性的剔除Nolz-1表現後，Satb1的表現下降於黑質區，卻使得Adcyap1、vGlut2、以及Calb1的表現上升（均為腹側區的表徵）。這些結果可合理推測Nolz-1在腹側區可能促進多巴胺神經元表現腹側區表徵之表現，且抑制黑質區表徵的表現。在黑質區可能促進多巴胺神經元表現黑質區表徵之表現，且抑制腹側區表徵之表現。論文中第四部，著重於DAT-Cre專一性剔除Nolz-1老鼠之行為分析。一般空間活動量上控制組和Nolz-1剔除老鼠之間並沒有顯著差異。雖然獎勵回饋學習行為之檢測控制組和Nolz-1剔除老鼠之間也並無顯著差異，但由於此實驗老鼠數量較少，尚需等待較多老鼠的數量進行分析。值得注意的是，在逐漸加速的運動桿平衡學習中，專一性剔除Nolz-1老鼠與控制組相比之下其運動學習表現卻顯著上升。然而兩組老鼠的運動協調能力是並無表現差異。這些行為結果，可以推測，DAT-Cre專一性剔除Nolz-1老鼠中腦多巴胺投射至紋狀體的路徑（控制運動的迴路）似乎是受到影響的。總結以上實驗，我們的研究表示Nolz-1可能扮演著發育過程中調控中腦多巴胺神經元的角色。

Nolz-1 (Znf503/Zfp503, Mouse Genome Informatics) is a zinc finger-containing gene. Nolz-1 is a mammalian member of the evolutionarily conserved nocA/elb/tlp-1 (NET) family. Our laboratory has previously shown that Nolz-1 function as transcriptional repressor in N2A and ST14A neural cell lines. Other groups have also reported that Nolz-1 zebrafish homologues (Nlz1/Nlz2) and the chick homologue also function as transcriptional repressors in regulation of hindbrain and spinal cord development, respectively. Our group has previously found that Nolz-1 is expressed in dopamine neurons in the medial part of ventral tegmental area (VTA) of developing mouse midbrain. The goal of the present thesis was to characterize developmental regulation of dopamine neurons in the mouse midbrain. The first part of my thesis was to characterize Nolz-1 expression pattern in developing mouse ventral midbrain with immunohistochemistry and in situ hybridization. In E13.5 and E15.5, Nolz-1 mRNA and protein were expressed in TH+ cells in the medial part of ventral midbrain where VTA progenitors were located. By E18.5 and postnatal day (P) 0 at which time VTA and SNpc sub-regions were formed, Nolz-1 mRNA and protein were expressed in a subpopulation of VTA, but not in SNpc dopamine neurons. In P7 and P14, Nolz-1 mRNA and protein were continually expressed in VTA. Interestingly, Nolz-1 mRNA and protein were transiently detected in SNpc dopamine neurons at P7 and P14. In adulthood, Nolz-1 mRNA and protein were absent in both VTA and SNpc. The second part of my thesis was to investigate whether midbrain Nolz-1-positive neurons were glutamatergic and GABAergic and the efferent targets to which Nolz-1-positive dopamine neurons project their axons. Triple labeling of Nolz-1, TH and vGlut2 showed that Nolz-1-positive dopamine neurons contained low level of vGlut2 mRNA. To label GABAergic neurons, we used GAD2-Cre;Ai14 mice. Nolz-1 was not co-localized in GABAergic neurons marked with tdTomato. We also performed retrograde axonal tracing experiments to identify the efferent targets of Nolz-1-positive dopamine neurons in VTA. CTB-Alxexa488 tracers were injected into the medial prefrontal cortex, nucleus accumbens, septum and amygdala of P2 brains, and the brains were analyzed at P7. The results showed that Nolz-1-positive dopamine neurons in VTA primarily projected their axons to the medial prefrontal cortex and septum with a lesser degree to the nucleus accumbens and amygdala. The third part of my study focused on molecular analysis of Nolz-1-positive dopamine neurons using loss-of-function and gain-of-function approaches. We first used Nestin-cre mice to drive Nolz-1 over-expression in neuronal cells. The percentage of VTA cells co-expressing TH and Otx2, a VTA marker, were increased, but the percentage of VTA cells co-expressing TH and Sox6, a SNpc marker, was decreased, suggesting that Nolz-1 over-expression may promote specification of the VTA dopamine cell type. However, over-expression of Nolz-1 did not affect Otx2 and Sox6 expression in SNpc neurons. We further used DAT-Cre mice to drive over-expression and conditionally knockout Nolz-1 in postmitotic dopamine neurons, In the VTA region, DAT-Cre-mediated over-expression of Nolz-1 increased Otx2 expression at Level 5, but had no effect on Sox6. There was a trend of increase of calbindin, a VTA marker, in VTA at Level 5. In the SNpc region, DAT-Cre-mediated ectopic expression of Nolz-1 decreased Sox6 expression at Level 5, but had no effect on Otx2. There was a trend of increase of calbindin in SNpc at Level 5. These findings suggest that over-expression of Nolz-1 in VTA may enhance VTA cell type phenotype and that ectopic expression of Nolz-1 in SNpc may induce VTA cell type-like phenotype in SNpc dopamine neurons. On the other hand, DAT-Cre-mediated knockout of Nolz-1 decreased Otx2, marker of VTA, in VTA, but increased Sox6, Satb1, and Girk2, markers of SNpc, in VTA. In contrast, DAT-Cre-mediated knockout of Nolz-1 decreased Satb1, marker of SNpce, in SNpc, but increased Adcyap1, vGlut2, and Calb1 markers of VTA, in SNpc. Our findings suggest that in VTA dopamine neurons Nolz-1 may promote VTA cell type phenotype, and suppress SNpc cell type-like phenotype. In SNpc dopamine neurons, Nolz-1 may promote SNpc cell type phenotype, and suppress VTA cell type phenotype. The fourth part of my thesis focused on behavioral analyses of Nolz-1 conditional knockout (CKO) mice. There was no difference in the locomotor activity between the controls and CKO mice. Although, the reward learning appeared to be not affected in Nolz-1 CKO mice as determined by the conditioned place preference task, the results await to be confirmed with larger sizes of the tested mice. Notably, motor learning was enhanced in Nolz-1 CKO mice as determined by accelerating rotarod task. The motor coordination was not affected in Nolz-1 CKO mice as determined by the constant speed rotarod task. Taken together, the dopamine mesosriatal pathway (motor circuits) seems to be affected in Nolz-1 CKO mice. In summary, our studies suggest that Nolz-1 may play a role in developmental regulation of dopamine neurons in the mouse midbrain.

Contents I
中文摘要 IX
Abstract XII
Chapter 1: Introduction 1
1.1 Importance of the midbrain dopamine systems in neurologic and psychiatric diseases 1
1.2 Heterogeneity of dopamine neurons in the ventral midbrain underlie diverse neurologic functions 1
1.3 Nolz-1/Zfp503 transcriptional regulator 2
1.4 A potential role of Nolz-1 in development of midbrain dopamine neurons 3
1.5 Aim of this thesis study 3
Chapter 2: Methodology 5
2.1 Animals 5
2.2 PCR genotyping of transgenic mice 5
2.3 Preparation of brain tissue 6
2.4 Cryostat 6
2.5 Immunohistochemistry 6
2.6 In situ hybridization with digoxigenin-labeled probes 7
2.7 Retrograde tracing by CTB injection 8
2.8 The Photobeam activity system for open field assay 9
2.9 Rotarod tasks 9
2.10 Conditioned place preference 10
2.11 Definition of anatomical levels 11
2.12 Quantification 11
Chapter 3: Results 13
3.1 Ontogeny of Nolz-1 mRNA and protein expression in the ventral midbrain during development 13
3.2 Characterization of Nolz-1+ neurons co-expressing other neurotransmitters in the ventral midbrain 14
3.3 Axonal projection targets of Nolz-1-posiive neurons in the ventral midbrain 15
3.4 Loss of function study of Nolz-1 in developing ventral midbrain 16
3.5 Gain of function study of Nolz-1 in developing ventral midbrain 17
3.6 Ectopic expression of Nolz-1 in SNpc did not affect expression of Otx2 and Sox6 19
3.7 Transgenic over-expression of Nolz-1 did not affect the expression of VTA marker calbindin in developing ventral midbrain 19
3.8 Conditional over-expression Nolz-1 in post-mitotic dopamine neurons increased Otx2 expression in VTA, but did not affect Otx2 expression in SNpc 20
3.9 Conditional over-expression Nolz-1 in post-mitotic dopamine neurons decreased expression of Sox6 in SNpc, but did not affect Sox6 expression in VTA 21
3.10 Conditional over-expression Nolz-1 in post-mitotic dopamine neurons did not alter expression of Calb in VTA, while there was a trend of Calb increase in SNpc 22
3.11 Otx2 was decreased in VTA DA neurons of P14 Dat-Cre;Nolz-1f/f;EGFP+ conditional knockout mice 22
3.12 Girk2 is increased in VTA dopamine neurons of P14 Dat-Cre;Nolz-1f/f;EGFP+ conditional knockout mice 23
3.13 Calbindin was increased in SNCD dopamine neurons of P4 Dat-Cre;Nolz-1f/f;EGFP+ conditional knockout mice 23
3.14 Sox6 was increased in VTA DA neurons of P4 Dat-Cre;Nolz-1f/f;EGFP+ conditional knockout mice 24
3.15 vGlut2 is increased in SNCD dopamine neurons of P4 Dat-Cre;Nolz-1f/f;EGFP+ conditional knockout mice 25
3.16 Conditional knockout of Nolz-1 in post-mitotic dopamine neurons increased Adcyap1+dopamine neurons in both PBP of VTA, and SNCD of SNpc in P4 Dat-Cre;Nolz-1f/f;EGFP+ mice 25
3.17 Conditional knockout of Nolz-1 in post-mitotic dopamine neurons decreased Satb1+ dopamine neurons in SNCD, but increased Satb1+ cells in PBP of VTA in P4 Dat-Cre;Nolz-1f/f;EGFP+ mice 26
3.18 Motor learning was enhanced in Dat-Cre;Nolz-1f/f CKO mice as determined by accelerating rotarod task 27
3.19 Reward learning was not affected in Dat-Cre;Nolz-1f/f CKO mice as determined by the conditioned place preference tasks 28
3.20 Locomotor activity was not altered in Dat-Cre;Nolz-1f/f CKO mice 29
Chapter 4: Discussion 30
4.1 Persistent expression of Nolz-1 in a subpopulation of dopamine neurons in VTA versus postnatal transient expression of Nolz-1 in SNpc dopamine neurons 30
4.2 Nolz-1-positive dopamine neurons are glutamatergic neurons co-expressing vGlut2 31
4.3 Nolz-1-positive midbrain dopamine neurons preferentially project axons to mPFC and septum 32
4.4 Nolz-1 plays a role in differentiation of subtypes of dopamine neurons 32
4.5 Over-expression of Nolz-1 specifically in post-mitotic dopamine neurons alters cell type identities in VTA and SNpc 33
4.6 Nolz-1 may promote VTA cell type identity, and simultaneously suppress expression SNpc cell type identity in VTA dopamine neurons 34
4.7 Nolz-1 may up-regulate SNpc cell type identity, and simultaneously suppress VTA cell type identity in SNpc dopamine neurons 35
4.8 Nolz-1 may control development of VTA dopamine cell types through Otx2 35
4.9 Behavioral analyses of motor learning and reward learning in Dat-Cre;Nolz-1f/f knockout mice 36
References 39
Figure and Figure legends 47
Figure 1. Expression of Nolz-1 in dopamine neurons of E13.5 mouse ventral midbrain 48
Figure 2. Expression of Nolz-1 in dopamine neurons of E15.5 mouse ventral midbrain 49
Figure 3. Nolz-1 is expressed in VTA, but not in SNpc dopamine neurons in ventral midbrain of P0 mice 50
Figure 4. Nolz-1 is persistently expressed in VTA dopamine neurons, but transiently in SNpc dopamine neurons in ventral midbrain of P7 mice 52
Figure 5. Nolz-1 is persistently expressed in VTA dopamine neurons, but transiently in SNpc dopamine neurons in ventral midbrain of P14 mice 54
Figure 6. Nolz-1 is absent in VTA and SNpc dopamine neurons in ventral midbrain of adult mice 56
Figure 7. RNA in situ hybridization for vGlut2 to identify glutamatergic neurons 57
Figure 8. RNA in situ hybridization for vGlut2 to identify glutamatergic neurons 59
Figure 9. RNA in situ hybridization for vGlut2 to identify glutamatergic neurons 61
Figure 10. Characterization of GAD2-Cre Expression in the midbrain of P14 mice 63
Figure 11. Retrograde tracing Nolz-1-projecting VTA-DA neuron 65
Figure 12. Validation of ectopic over-expression Nolz-1 in E18.5 ventral midbrain 67
Figure 13. E18.5 VTA was divided into 7 anatomical levels along the rostrocaudal axis in TG and nCT 69
Figure 14. Over-expression of transgenic Nolz-1 increases Otx2 expression in VTA of E18.5 midbrain 70
Figure 15. Over-expression of transgenic Nolz-1 on Sox6 expression in VTA of E18.5 midbrain 72
Figure 16. Ectopic expression of transgenic Nolz-1 on Otx2 expression in SNpc of E18.5 midbrain 74
Figure 17. Ectopic expression of transgenic Nolz-1 on Sox6 expression in SNpc of E18.5 midbrain 76
Figure 18. Ectopic expression of transgenic Nolz-1 on Calb expression in VTA of E18.5 midbrain 78
Figure 19. Ectopic expression of transgenic Nolz-1 on Calb expression in SNpc of E18.5 midbrain 80
Figure 20. Validation of conditional over-expression Nolz-1 in E18.5 ventral midbrain 83
Figure 21. E18.5 VTA was divided into 7 anatomical levels along the rostrocaudal axis in TG and DAT-TG 85
Figure 22. Over-expression of Nolz-1 by Dat-Cre recombinased in post-mitotic cells of VTA in E18.5 midbrain 86
Figure 23. Over-expression of Nolz-1 by Dat-Cre recombinase in post-mitotic cells of SNpc in E18.5 midbrain 88
Figure 24. Over-expression of Nolz-1 by Dat-Cre recombinase in post-mitotic cells of SNpc in E18.5 midbrain 91
Figure 25. Over-expression of Nolz-1 by Dat-Cre recombinase in post-mitotic cells of VTA in E18.5 midbrain 93
Figure 26. Over-expression of transgenic Nolz-1 on Calb expression in VTA of E18.5 midbrain 95
Figure 27. Over-expression of transgenic Nolz-1 on Calb expression in SNpc of E18.5 midbrain 97
Figure 28. Midbrain of P4 mice was divided into 6 anatomical levels along the rostrocaudal axis in control and CKO 99
Figure 29. Otx2 is decreased in VTA DA neurons of P14 101
Figure 30. Girk2 is increased in VTA dopamine neurons of P14 Dat-Cre;Nolz-1f/f;EGFP+ conditional knockout mice 103
Figure 31. vGlut2 is increased in SNCD dopamine neurons of P4 Dat-Cre;Nolz-1f/f;EGFP+ conditional knockout mice 105
Figure 32. Adcyap1 is increased in VTA dopamine neurons of P4 Dat-Cre;Nolz-1f/f;EGFP+ conditional knockout mice 107
Figure 33. Satb1 is increased in VTA dopamine neurons of P4 Dat-Cre;Nolz-1f/f;EGFP+ conditional knockout mice 111
Figure 34. The enhancement of motor skill learning in Dat-Cre;Nolz-1f/f mice 114
Figure 35. The preference of place conditioning in Dat-Cre;Nolz-1f/f mice 116
Figure 36. Locomotor activity in the open field 118
Figure 37. Nolz-1 plays a role in differentiation of subtypes of dopamine neurons 119
Figure 38. Working hypothesis of Nolz-1regulation of subtype dopamine neurons in the ventral mouse midbrain 121
Tables 123
Table 1. Summary of the results of IHC/ISH 124
Table 2. Summary of the changes of VTA and SNpc markers in Nolz-1 mutant mice and Nolz-1 over-expression transgenic mice 125
Table 3. Locomotor activity in theopen field 126
Table 4. Potential changes of the genes related to dendritic spine formation in the dorsomedial striatum of Dat-Cre; Nolz-1fl/fl mice as revealed by RNA-seq analysis 129
Table 5. Antibody condition 130
Table 6. Genotyping primer sequences and related conditions 131
Table 7. Summary of the cRNA probes for in situ hybridization 132
Table 8. Raw data of quantification of Otx2 expression in SNpc of E18.5 midbrain 133
Appendixes 134

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