Heixuedian (heix), a potential melanotic tumor suppressor gene, exhibits specific spatial and temporal expression pattern during drosophila hematopoiesis

Abstract

The Drosophila heixuedian (heix) is the ortholog of human UBIAD1 gene (a.k.a TERE1). The protein product of UBIAD1/heix has multiple enzymatic activities, including the vitamin K2 and the non-mitochondrial CoQ10 biosynthesis. However, the expression pattern of UBIAD1/Heix during metazoan development has not been systematically studied. In this paper, we found that loss of function of heix resulted in pathological changes of larval hematopoietic system, including lymph gland hypertrophy, hemocyte overproliferation and aberrant differentiation, and melanin mass formation. Overexpression of heix cDNA under the tubulin Gal4 driver rescued the above hematopoietic defects. Interestingly, Heix was specifically expressed in plasmatocyte/macrophage lineage in srp driven EGFP positive cells on the head mesoderm during embryogenesis, while it was highly expressed in crystal cells in the primary lobes of the third instar larval lymph gland. Using qRT-PCR analysis, loss of function of heix caused aberrant activation of multiple hemocyte proliferation-related as well as immune-related pathways, including JAK/STAT pathway, Ras/MAPK pathway, IMD pathway and Toll pathway. These data suggested that heix is a potential melanotic tumor suppressor gene and plays a pivotal role in both hemocytes proliferation and differentiation in Drosophila.

Functional Characterization of the Vitamin K2 Biosynthetic Enzyme UBIAD1

“…Whether UBIAD1 has other functions beside the synthesis of MK-4 is unknown. UBIAD1/ubiad1 mutations in zebrafish have been reported to cause cardiac oedema and cranial haemorrhages [ 16 , 18 ] and UBIAD1/heixuedian mutations in Drosophila cause defects in mitochondrial ATP production [ 10 , 19 ]. Missense mutations in UBIAD1 are the underlying cause of the human genetic disorder Schnyder corneal dystrophy (SCD).…”

Vitamin K2 Prevents Lymphoma in Drosophila

“…1A ). heix mutant larvae often die at the pupal stage 13 . Interestingly, in our research, third-instar larvae fed with VK2 showed significantly increased pip-out rates (*** P < 0.001) and a strong response to VK2 (Fig.…”

“…1B ). heix mutation is associated with impaired flight 14 and reduced activity 13 . Similarly, we observed a significant decrease in movement speed (*** P < 0.001) (Fig.…”

“…Drosophila heixudian “ heix ” gene encodes a protein that bears high sequence identity with the human UBIAD1 protein, loss-of-function of UBIAD1 tends to progress bladder and prostate carcinoma 12 . Loss-of-function of heix leads to hemocyte overproliferation and aberrant differentiation 13 . heix mutants showed severe mitochondrial defects, and VK2 transfers electrons in Drosophila mitochondria, thus improving ATP production 14 .…”

“…Plasmatocytes and lamellocytes, which function in encapsulation, are rare in healthy larvae 22 . The activation of the JAK/STAT and immune-related pathways Toll and IMD is associated with the loss-of-function of UBIAD1 / heix 13 in lymphoma and leukemia 23 .…”