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Expression pattern analysis of coronary and lymphatic vessel genes in zebrafish and mice
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Expression pattern analysis of coronary and lymphatic vessel genes in zebrafish and mice
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1
Expression pattern analysis of coronary and
lymphatic vessel genes in zebrafish and mice
By
Jingling Hou
Mentor: Ching-Ling Lien, Ph.D.
A Thesis Presented to the
FACULTY OF THE USC GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the Requirements for the Degree
MASTER OF SCIENCE
(Biochemistry and Molecular
Medicine)
December 2018
1 Department of Biochemistry & Molecular Medicine, Keck
School of Medicine, University of Southern California, 90033
CA, USA
2 Heart Institute and Saban Research Institute and Program of
Developmental Biology and Regenerative Medicine,
3 Department of Surgery, Keck School of Medicine,
University of Southern California
2
Table of Contents
ABSTRACT ............................................................................................................................. 3
CHAPTER ONE: INTRODUCTION .................................................................................... 3
GENERAL INTRODUCTION OF LYMPHATIC VESSEL ................................................................... 3
ROLE OF CARDIAC LYMPHATIC VASCULATURE IN MYOCARDIAL INFARCTION ........................ 4
DEVELOPMENT OF THE MOUSE LYMPHATIC VASCULATURE ..................................................... 5
DEVELOPMENT OF CARDIAC LYMPHATIC VASCULATURE IN ZEBRAFISH .................................. 7
THE ROLE OF CXCR4A IN CARDIAC LYMPHATIC DEVELOPMENT IN ZEBRAFISH ........................ 9
HYPOTHESIS .......................................................................................................................... 10
CHAPTER TWO: MATERIAL AND METHOD .............................................................. 11
REAGENT .............................................................................................................................. 11
SOLUTION FORMULATION ..................................................................................................... 12
METHOD ............................................................................................................................... 14
RNA-seq data analysis ..................................................................................................... 14
Biotagging model ............................................................................................................. 15
Test the germline transmission ........................................................................................ 15
Whole mount staining ...................................................................................................... 16
CHAPTER THREE: RESULTS .......................................................................................... 17
RNA-SEQ DATA ANALYSIS FROM CXCR4A MUTANT ZEBRAFISH AND THE WILD TYPE ........... 17
ZEBRAFISH FOUNDER SCREENING ......................................................................................... 21
WHOLE MOUNT IMMUNOSTAINING ........................................................................................ 21
CHAPTER FOUR: DISCUSSION AND FUTURE DIRECTION .................................... 22
REFERENCES ....................................................................................................................... 23
3
Abstract
The role of the cardiac lymphatic vessel during heart development has been appreciated
recently, since cardiac lymphatic vessel may be involved in wound healing after heart injury
in mouse. However, the formation and maturation of the cardiac lymphatic vessel have not
been fully understood. According to Klotz et al, the lymphatic vessels are associated with
coronary veins in mouse. Previous data from our lab showed that the cardiac lymphatic
vessels are associated with coronary arteries in zebrafish. It has been reported that the cardiac
lymphatic vessels development is associated with coronary arteries in human. My hypothesis
is that cardiac lymphatic development in zebrafish may be different with that in mouse. My
project has two parts to test my hypothesis. First, I analyzed the RNA-seq data from cxcr4a
mutant heart to distinguish the genes that are expressed in lymphatic cell from coronary
endothelial cell. Second, I used the immunofluorescent staining to determine whether the
expression pattern of these candidate genes found in first aim is conserved in mouse.
Key works: Cardiac lymphatic vessel, Coronary vessel,
cardiac artery, cxcr4a, CD31, prox1
Chapter one: Introduction
General introduction of lymphatic vessel
Lymphatic system is an elaborate network of vessels, which are involved in protecting us
from the disease. Unlike blood vessels, lymphatic vessels start as pockets rather tubes.
Lymph flow from lymphatic capillaries to larger lymphatic vessels containing one-way
valves. Lymphatic vessels carry the lymph from the peripheral tissue to the venous system to
4
maintain the homeostasis and provide a route for leukocytes and lipids transportation. Defects
in lymphatic function can lead to lymph accumulation in tissues, dampened immune
responses, connective tissue and fat accumulation, and tissue swelling known as lymphedema
[1]
. Lymphangiogenesis is important in chronic inflammatory cancer metastasis, and
lymphedema, so many potential therapeutic strategies are targeting lymphatic vessels. In
most cases, the origin of the lymphatic vasculature is venous endothelial cells. A recent study
reveals that the origins of mouse cardiac lymphatic vessels might be heterogeneous
[2]
.
Besides venous endothelial cells, the progenitor of LEC might be from hemogenic
endothelium
[2]
.
Role of cardiac lymphatic vasculature in Myocardial Infarction
Myocardial infarction (MI) is also known as heart attack, primarily caused by the blockage of
coronary artery, causing an interruption of blood flow and the death of a section of
myocardium being supplied by the artery. Collagen scars form at that place. Death of
myocardium and collagen scars weaken the normal heart function. Lymphangiogenesis was
observed in human and murine model post-MI. treatment with VEGF-C post-MI can enhance
the lymphangiogenesis and improve the cardiac function
[3]
. Although the mechanism is still
unknown, targeting the lymphatic vasculature might provide therapeutic clues.
5
Figure 1. Treatment with recombinant VEGF-C following MI in a murine model leads to
enhanced lymphangiogenesis and improved cardiac function. (Norman, S, et al. Clin Anat.
29(2016):305-15.)
Development of the mouse lymphatic vasculature
There are several important regulators involved in development of mouse lymphatic
vasculature. COUP transcription factor 2 (COUP-TFII) is expressed in all venous cells. Sox
18 is a transcription factor, involved in regulation of embryonic development. Prox1 is
activated by COUP-TFII and Sox18, which determines the specification of lymphatic
endothelial cells (LEC) from venous precursor cells. The expression of Vascular endothelial
growth factor receptor-3 (VEGFR-3) induces the budding and migration of LECs along the
gradient of VEGFC
[4]
.
Figure 2. Schematic representation of the development of mammalian lymphatic vasculature.
(Huang, Lavine, & Randolph. (2017). Cardiac Lymphatic Vessels, Transport, and Healing of
the Infarcted Heart. JACC: Basic to Translational Science, 2(4), 477-483.)
At E9.0, all venous endothelial cells express COUP-TFII. At E9.5, COUP-TFII and SOX 18
activates the expression of PROX1 in some venous endothelial cells, considered as LEC
progenitors. They are designated for lymphatic endothelial cell specification. At E10.5, the
6
budding and migration of LECs requires VEGF-C. Mediated by PROX1, the expression of
VEGFR-3 induces the budding and migration of LECs along the VEGF-C towards venous
sinus. At E11.5, the budded LECs assemble together to form lymph sac
[4]
.
The development of cardiac lymphatic vasculature in mice is shown in figure 3. The
lymphatic endothelial cells are marked by Prox1 in green and VEGFR-3 in red. LECs enter
the heart by embryonic day E12.5 The emergence of lymphatic vessels were observed at
E12.5 proximal to the outflow tract on ventral side. By E14.5, on the dorsal side of ventricle,
the lymphatic vessels were observed sprouting from the region of sinus venosus. After that,
the lymphatic networks expand from the base of the heart to the apex of heart. By postnatal
day P15, the cardiac lymphatic networks are fully developed.
In figure 4, the lymphatic vessels are marked by LYVE-1 in red and the coronary veins are
marked by Emcn in green. This figure shows the cardiac lymphatic vessel is aligned with the
coronary veins by E17.5. therefore, the lymphatic vessels are associated with coronary vein
in mice.
Figure 3. The development of cardiac lymphatic vasculature in mouse. Whole-mount
7
confocal imaging of embryonic hearts stained with VEGRF-3 (lymphatics) and Prox1
(lymphatics). (Klotz, L. et al Nature. 522(2015):62-7.)
Figure 4. Development of mouse cardiac lymphatic vasculature. Whole-mount staining with
endomucin (Emcn, veins) and LYVE-1 (lymphatics). (Klotz, L. et al Nature. 522(2015):62-
7.)
Development of Cardiac lymphatic vasculature in zebrafish
The development of systemic lymphatic vasculature in zebrafish is similar to that in mice.
However, there are very few studies describing cardiac lymphatic vessels in zebrafish. Unlike
mouse, no cardiac lymphatic vessel was found in zebrafish hearts during embryonic and early
8
juvenile stage. In our lab, Dr. Michael Harrison, a postdoctoral fellow found cardiac
lymphatic vessel development at late juvenile and adult stage in zebrafish. Several transgenic
reporter lines have been used to characterize development. The results are shown in figure 4.
He found that vessels marked by flt4:mCitrene are mainly restricted covering the bulbous
arteriosus at 115 dpf and expanded from the base of heart to the apex of the 162 dpf.
flt4:mCitrene transgenic line marks both venous and lymphatic vessels, so in order to check
the identity of the vessel marked by flt4:mCitrene, Prox1:RFP transgenic line was used by
Michael. The co-expression of Prox1 and Flt 4 confirms that the vessels are lymphatic
(Figure 5 D-F). In zebrafish, the cardiac lymphatic vessels marked by flt4:mCitrene seemed
aligned with the coronary artery reported by flt1:tdTomato (Figure 5 G). This observation
was confirmed in stage 162dpf (Figure 5 H-I). The lymphatic vessel marked by Prox1:RFP
enwind the artery marked by kdrl:mTurquoies. Unlike in mice, the cardiac lymphatic vessels
are associated with coronary arteries in zebrafish.
9
Figure 5. Development of zebrafish cardiac lymphatic vasculature. Confocal images of the
adult transgenic hearts, Tg(fli:GFP;flt4:mCitrene)(A-C),
Tg(fli:GFP;prox1:RFP;flt4mCitrene)(D-F), Tg(flt:GFP;flt4:mCitrene;flt1:tdTomato)(G),
and Tg(flt:GFP;kdrl:mTurquoies;prox1:RFP)(H-I). flt4:mCitrene and fli:GFP positive
endothelial cells are migrate down from the bulbous arteriosus to ventricle (A-C). fli:GFP,
prox1:RFP and flt4:mCitrene positive vessels are lymphatics (D-F). prox1:RFP-positive
lymphatic vessels are aligned with kdrl:mTurqoies-positive coronary arteries (H-I). Credit:
Dr. Michael Harrison.
The role of Cxcr4a in cardiac lymphatic development in zebrafish
Michael found another interesting phenotype in cxcr4a mutant zebrafish. Compared with
cxcr4a heterozygous zebrafish, lymphatic endothelial vessels and coronary arteries were not
present on ventricle (Figure 6 A-D). The mechanism of disappearance of both lymphatic
vessels and arteries in cxcr4a mutant in zebrafish is unknown. Since cxcr4a mutants show
defects in coronary vessel development
[5]
, there are two possible mechanisms underlying the
lymphatic defects of cxcr4a mutants. First, cxcr4a has cell autonomous roles in lymphatic
vessels. Second, the development of cardiac lymphatic vessels depends on the coronary
artery and the defects in lymphatic vessels in cxcr4a mutants are secondary to the coronary
vessel phenotypes.
10
Figure 6. cxcr4a is required for development of cardiac lymphatic vasculature
Fli:GFP-positive endothelial cells are spread on the ventricle but fail to form the cardiac
lymphatic vessels on ventricle (A, cxcr4a heterozygous zebrafish and B,cxcr4a mutant). Both
coronary arteries and cardiac lymphatics disappeared on cxcr4a -/-(C, cxcr4a +/+ and D,
cxcr4a -/-). Credit: Dr. Michael Harrison.
Hypothesis
According to Klotz et al, the lymphatic vessels are associated with coronary veins in mouse
(2015). Previous data from our lab showed that the cardiac lymphatic vessels are associated
with coronary arteries in zebrafish. It has been reported that the cardiac lymphatic vessels
11
development is associated with coronary arteries in human. Therefore, my hypothesis is that
cardiac lymphatic vessels associate with coronary arteries in zebrafish while they may
associate with veins and arteries in mice and humans during heart development.
Chapter two: Material and Method
Reagent:
KCl Sigma
NaCL Sigma
Na
2
HPO
4
Sigma
TRIzol Ambion
Na
2
HPO4 Sigma
Tricaine Sigma
NaOH Sigma
Low melting point agarose Fisher Bioregents
DMSO Sigma
H
2
O
2
Sigma
Horse serum Sigma
16% paraformaldehyde (PFA) Electron Microscopy Sciences
100% Ethanol PHAMCO-AAPER
12
Alexa Fluor
®
594 anti-rabbit IgG Invitrogen
Alexa Fluor
®
488 anti-mouse IgG Invitrogen
Alexa Fluor
®
568 anti-rabbit IgG Invitrogen
CD31(MEC 13.3) antibody BD Biosciences Pharmingen
Prox1 antibody R&D systems
Podoplanin antibody DSHB
CXCR4 antibody NOVUS
Solution Formulation:
Dent’s Fix
DMSO 50mL
NaOH 200mL
Dent’s Bleach
H
2
O
2
25mL
Dent’s Fix 50mL
Blocking serum
5% heated inactivated Horse serum
75% PBS
13
20% DMSO
10x PBS:
NaCl 80g
KCl 2g
Na
2
HPO
4
14.4g
dH
2
O to 1L
pH=7.4
1x PBS:
10x PBS 100ml
dH
2
O to 1L
1x PBST:
10x PBS 100ml
Tween 20 1ml
ddH
2
O to 1L
pH=7.4
Tricaine:
Tricaine 4g
1M Tris-HCl(pH=9) 21ml
14
ddH
2
O to 1L
pH=7.4
4% PFA in PBS
16% paraformaldehyde (PFA) 10ml
1xPBS to 40ml
store at 4
1% Agarose in PBS
low melting point agarose 1g
1xPBS 100ml
80% ethanol
100% ethanol 8ml
dH
2
O 2ml
Method
Aim 1, analyzed the RNA-seq data from 4-mounth old-cxcr4a mutant and wildtype zebrafish
ventricle to identify the differentially expressed genes. Then I will use the biotagging model
to analyze genes expressed specifically in coronary endothelial cells or lymphatic cells
respectively.
RNA-seq data analysis
Michael Harrison in our lab collected the whole ventricle from 4-mounth old cxcr4a mutant
and wildtype zebrafish respectively and did the RNA-seq. I used the ggplot2 library in R to
15
make volcano plot to show the difference expression. Gene list analysis and Enrichment
analysis was performed by using Panther system
[6]
.
Biotagging model
Figure 7. Schematic of the binary transgenic system for cell-type-specific in vivo
biotinylation. BirA drivers are in red and Avi effector lines in blue. POI, protein of interest.
(Trinh, Le A. et al. Biotagging of Specific Cell Populations in Zebrafish Reveals Gene
Regulatory Logic Encoded in the Nuclear Transcriptome. Cell Reports, 19(2), 425-440).
Biotagging is a binary in vivo biotinylation system in zebrafish
[7]
. There are two transgenic
lines in this system. One is driver line, which can express Biotin in tissue-specific manner,
the other is effector line, which can express Avi-tag conjugated with protein of interest. Cross
this two lines together and get the embryo. If the specific cells in the embryo can express
both BirA and Avi-tag. Avi-tag can be biotinylated by BirA and the biotinylated protein of
interest can be captured by streptavidin magnetic beads. In this case the protein of interest
could be either nuclear envelop protein or ribosome protein. Therefore, the ribosome and
nucleus can be isolated and then the transcriptome profiling in those cells can be carried
out
[7]
.
Test the germline transmission
After generating the transgenic lines that will be used in biotagging model, determining
germline transmission of the transgene is required. Currently, our collaborator Dr. Trinh have
16
the kdrl:BirA founders. Cross 6 female kdrl:BirA founders with AB/TL male zebrafishes and
cross male kdrl:BirA founders with AB/TL female zebrafishes in breeding tank in the
afternoon overnight. The embryos were collected in the petri dish in the following morning
and placed the dish in an incubator at 28.5 overnight. In the following afternoon, the specific
expression pattern of kdrl was checked.
Aim 2, I used the immunofluorescent staining to determine whether the expression pattern of
these candidate genes found in zebrafish is conserved in mouse and human.
Whole mount staining
Dissect the E16.5 embryonic mouse heart in ice-cold PBS. Fix in fresh 4% paraformaldehyde
(PFA) in PBS at 4 for 24 hours. Rinse it three times in PBS. Dehydrate the tissue stepwise
in methanol (20%, 40%, 60%, 80% and 100% for 60 minutes at each step.) Storage the heart
in 100% methanol overnight. Incubate the heart in Dent’s bleach overnight at 4℃. Rinse it 5
times in MeOH and fix it in Dent’s Fix at least 24 hours at 4℃. Rinse it 3 times in PBS and
wash 3 times in PBS once per hour. Apply the primary antibody (CD31(553370, BD
pharminigen, 1:50), PROX1 (AF2727, R&D Systems, 1:200), Podoplanin (8.1.1, DSHB,
1:200), CXCR4 (NLS1380, NOVUS, 1:200) in blocking solution, and incubate at room
temperature 3-5 days. Rinse 3 times in PBS and wash 5 times in PBS once per hour. Apply
the AlexaFluor secondary antibody (Invitrogen, 1:200) in blocking solution, incubate at room
temperature overnight. Wash 5 times in PBS one hour for each time. Add the 1% low melting
agarose in PBS on the deep dish with glass cover. Embed the tissue into agarose. Images are
done by Zeiss LSM710 confocol microscope.
17
Chapter three: Results
RNA-seq data analysis from Cxcr4a mutant zebrafish and the wild type
I analyzed the RNAseq data using the DAVID analysis (https://david.ncifcrf.gov/)
[6]
.
A total of 28514 genes showed detectable levels of expression in 4-month old cxcr4a mutants
and WT. There are 2160 differentially expressed genes with FDR corrected p-value< 0.05,
in which, 741 genes are up-regulated and 1419 genes are down regulated with a &'(
)
(FC) ≥
1 or ≤ −1 cut off (Figure. 8)
Figure 8. The volcano plot of differentially expressed genes in 4-month old cxcr4a mutants
and wild type zebrafishes. Vertical and horizontal lines reflect the filtering criteria
(FC=±2 and p-value=0.05). Green dots represent down-regulated genes. Red dots represent
up-regulated. Blue dots refer to no differential expression.
Then utilize PANTHER to do the functional classification in gene list. Out of 2160
differential expressed genes, 358 genes are not annotated in any GO groups. The rest 1802
genes are analyzed by three functional groups: Biological process, Molecular function and
18
Cellular component. Within each functional classification, DEGs involved in “cellular
process”, “metabolic process” and “biological regulation” are dominant amount biological
process; “translational regulator activity” and “binding” are predominant among molecular
function, “cell part” and “organelle” are predominant among cellular component.
Figure 9. Functional annotation of differentially expressed genes in GO PANTHER.
The 1419 down-regulated genes were further applied to the PANTHER enrichment analysis.
1168 differentially expressed genes are mapped to GO annotation, while 251 genes are
unmapped. In GO terms for biological processes and molecular function enrichment with p <
0.05. Majority of the GO terms are related to the lymphatic functions (Figure 10A.), which
are consistent with Michael’s observation that lymphatics vessels failed to form on the
ventricle of cxcr4a mutants. Chemokine related GO terms played a predominant role in
molecular function enrichment analysis (figure 10B). The genes related to chemokine
receptor binding and chemokine activity enriched in immune response term shown in (figure
19
10C). Therefore, the chemokine-mediated signaling pathway, chemokine receptor binding
and chemokine activity can be related to both lymphatic and coronary endothelial cells.
20
Figure 10. Top 20 of biological process (A) and molecular function (B) by GO analysis of
down-regulated genes, FDR<0.05. (C) Genes enriched in immune response are related to
chemokine activity and receptor binding
There over 120 genes are involved in immune system process. 29% of those genes express
signaling molecules. Majority of those signaling molecules contain the chemokine motif.
Figure 11 Protein class of genes in immune system process cluster
21
Zebrafish founder screening
We have crossed 12 pairs of fish founders. 8 pairs gave eggs. Embryos at 32dpf from one pair
have specific fluorescent signal for kdrl, the bright white signal shown under the head (Figure
A and B). The images are provided by Paul Yim in Dr. Le Trinh’s lab.
Figure 12. A lateral view of the entire zebrafish at 32hpf. B enlarged the image of A.
Whole mount immunostaining
I used CD31 antibody and Prox1 antibody in our lab with mouse embryo heart on E16.5 to
test whether these antibodies work well. CD31 markers the endothelial cells (Figure 13A).
The bright red coronary vessels are against the background (Figure 13). Lymphatic vessels in
blue are in granular pattern that are marked by Prox1 (Figure 13B). Michael applied prox1
antibody on human fetus heart using the same protocol (Figure 13C). The lymphatic vessels
are shown in bright white against the dark background.
22
Figure 13. A and B mouse embryo heart staining. Vessels are marked by CD31 and
lymphatic vessels are marked by prox1. C. human embryo heart staining (credit: Dr. Michael
Harrison).
Chapter four: Discussion and Future Direction
For my first aim, I found the down-regulated genes are involved lymphatic functions
like immune response. Further analysis of the genes in enriched clusters might reveal why
both cardiac lymphatics and coronary arteries fail to develop in cxcr4a zebrafish mutants. In
the future, biotagging model can be used to analyze cell-specific gene expression patterns,
e.g. cardiac lymphatics, or coronary arteries or both. I have screened the Kdrl: BirA founders
that have germline transmission. The biotagging process can first start with the coronary
vessels.
For my second aim, I have tried 4 antibodies. Among them, the PROX1 and CD31 antibodies
worked well on mouse embryonic heart. Same antibody PROX1 worked well on human fetal
hearts performed Michael. The whole-mount staining protocol worked on antibody RPOX1
and CD31. For other antibodies like Podoplanin and LYVE-1 that did not work well on
whole-mount staining, I can try cyrosection or paraffin section to test the them in the future.
23
References
[1] Kari Alitalo. (2011). The lymphatic vasculature in disease. Nature Medicine,17(11),
1371-80.
[2] Klotz, L., Norman, S., Vieira, J., Masters, M., Rohling, M., Dube, K., . . . Riley, P.
(2015). Cardiac lymphatics are heterogeneous in origin and respond to
injury. Nature,522(7544), 62.
[3] Norman, S., & Riley, P. (2016). Anatomy and development of the cardiac lymphatic
vasculature: Its role in injury and disease. Clinical Anatomy, 29(3), 305-315.
[4] Huang, Lavine, & Randolph. (2017). Cardiac Lymphatic Vessels, Transport, and Healing
of the Infarcted Heart. JACC: Basic to Translational Science, 2(4), 477-483.
[5] Harrison, Michael r.M., Bussmann, Jeroen, Huang, Ying, Zhao, Long, Osorio, Arthela,
Burns, C. geoffrey, . . . Lien, Ching-Ling. (2015). Chemokine-Guided Angiogenesis Directs
Coronary Vasculature Formation in Zebrafish. Developmental Cell, 33(4), 442-454.
[6] Da Wei Huang, Brad T Sherman, & Richard A Lempicki. (2008). Systematic and
integrative analysis of large gene lists using DAVID bioinformatics resources. Nature
Protocols,4(1), 44-57.
[7] Trinh, Chong-Morrison, Gavriouchkina, Hochgreb-Hägele, Senanayake, Fraser, & Sauka-
Spengler. (2017). Biotagging of Specific Cell Populations in Zebrafish Reveals Gene
Regulatory Logic Encoded in the Nuclear Transcriptome. Cell Reports, 19(2), 425-440.
Abstract (if available)
Abstract
The role of the cardiac lymphatic vessel during heart development has been appreciated recently, since cardiac lymphatic vessel may be involved in wound healing after heart injury in mouse. However, the formation and maturation of the cardiac lymphatic vessel have not been fully understood. According to Klotz et al, the lymphatic vessels are associated with coronary veins in mouse. Previous data from our lab showed that the cardiac lymphatic vessels are associated with coronary arteries in zebrafish. It has been reported that the cardiac lymphatic vessels development is associated with coronary arteries in human. My hypothesis is that cardiac lymphatic development in zebrafish may be different with that in mouse. My project has two parts to test my hypothesis. First, I analyzed the RNA-seq data from cxcr4a mutant heart to distinguish the genes that are expressed in lymphatic cell from coronary endothelial cell. Second, I used the immunofluorescent staining to determine whether the expression pattern of these candidate genes found in first aim is conserved in mouse.
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Hou, Jingling
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Core Title
Expression pattern analysis of coronary and lymphatic vessel genes in zebrafish and mice
School
Keck School of Medicine
Degree
Master of Science
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Biochemistry and Molecular Medicine
Publication Date
10/15/2020
Defense Date
07/30/2018
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