THESIS
2018
xiii, 119 pages : illustrations (chiefly color) ; 30 cm
Abstract
Microglia, the resident macrophages in CNS, play critical roles in maintaining CNS
development and homeostasis. Microglia begin to colonize the optic tectum of brain since
2.5 dpf in zebrafish, which is triggered by apoptotic neurons. When neurons undergo
apoptosis, they release LPC, a lysophospholipid acting as find-me signal and attracting
microglial precursors migrate into brain. However, LPC can be digested to LPA in vivo and
whether LPA have chemoattractant function for microglial colonization is still unknown. In
the first part of this thesis, we clarified that LPA signaling also involves in microglial
colonization process through LPA-LPARs axis.
After microglia initial colonize into brain, they play versatile functions in maintaining CNS
homeostasis. How microglia contri...[
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Microglia, the resident macrophages in CNS, play critical roles in maintaining CNS
development and homeostasis. Microglia begin to colonize the optic tectum of brain since
2.5 dpf in zebrafish, which is triggered by apoptotic neurons. When neurons undergo
apoptosis, they release LPC, a lysophospholipid acting as find-me signal and attracting
microglial precursors migrate into brain. However, LPC can be digested to LPA in vivo and
whether LPA have chemoattractant function for microglial colonization is still unknown. In
the first part of this thesis, we clarified that LPA signaling also involves in microglial
colonization process through LPA-LPARs axis.
After microglia initial colonize into brain, they play versatile functions in maintaining CNS
homeostasis. How microglia contribute to the CNS homeostasis still needs to be explored.
For the second part of this thesis, we uncovered microglial role in Type IV Mucolipidosis
(ML-IV), a neurodegenerative lysosome storage disorder which is caused by the mutation in
gene TRPML1 . Using forward genetic screening, we identified a zebrafish mutant, biluo ,
which harbors a hypomorphic mutation in trpml1a , the zebrafish ortholog of mammalian
TRPML1 . biluo mutants display phenotype partially recapitulating the key features of ML-IV
disorder including accumulation of enlarged late-endosomes in microglia and aberrant
neuronal activity in both spontaneous and visual-evoked situations in optic tectum neurons.
We further show that the accumulation of enlarged late-endosomes in microglia is largely
caused by the impairment of late-endosome and lysosome fusion and the aberrant neuronal activities can be partially rescued by the reconstitution of Trpml1a function in microglia. Our
findings provide the first evidence that dysregulation of microglia function may contribute
to the early stages of ML-IV disease progression, shedding lights on the disease mechanism
as well as the microglia-neuron interaction.
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