Title : Drosophila melanogaster as a model system to dissect the role of membrane trafficking in cytokinesis and human diseases

From : Institute of Molecular Biology and Pathology (IBPM), CNR –
Dept. of Biology and Biotechnologies , Sapienza University of Rome, Rome, Italy

When: Friday, January 24th at 12:00 p.m.CNR

Where : Conference Room – Research Area NA1 ( Naples )

Host: Dr. Parashuraman Raman 
Tel. 081/6132283; e-mail: r.parashuraman@ibp.cnr.it

A major focus of our research studies concerns the mechanisms underlying cytokinesis. Accurate control of cytokinesis represents a fundamental task in normal development and is also essential for maintaining ploidy and preventing neoplastic transformation. Cytokinesis errors have been associated with several human diseases including blood disorders, Lowe syndrome, female infertility and cancer. Thus, analysis of the molecular pathways involved in cytokinesis, might contribute to develop new therapeutic strategies against cancer and other diseases. Most of our studies are carried out in Drosophila melanogaster, which offer numerous advantages for combined genetic and cytological studies of the structural and morphological events that characterize cytokinesis. Cytokinesis requires a tight coordination between actomyosin ring constriction and new membrane addition along the ingressing cleavage furrow. However, the molecular mechanisms underlying vesicle trafficking to the equatorial site and how this process is coupled with the dynamics of the contractile apparatus, are poorly defined.

Golgi phosphoprotein 3 (GOLPH3) has been characterized as a Phosphatidylinositol 4-Phosphate [PI(4)P] effector at the Golgi, involved in vesicle trafficking and Golgi glycosylation. GOLPH3 is frequently amplified in several solid tumor types including breast cancer, melanoma and lung cancer. Moreover GOLPH3 overexpression is correlated with poor prognosis in multiple cancer types. However the molecular pathways through which GOLPH3 acts in malignant transformation require further investigation. We have demonstrated that GOLPH3 accumulates at the cleavage furrow and is essential for cytokinesis in Drosophila melanogaster. Our studies suggest that GOLPH3 might act as a key molecule in coupling vesicle trafficking with actomyosin ring assembly and stability during cytokinesis. To gain further insight into GOLPH3 function in vesicle trafficking during cytokinesis, we are analyzing the molecular interactions of GOLPH3 with regulators of endocytic/secretory pathways. Amongst the putative molecular interactors of GOLPH3, we have identified Rab1 and COG7, a subunit of the Conserved Oligomeric Golgi (COG) complex. The COG complex functions as a vesicle-tethering factor for intra-Golgi retrograde trafficking, playing a crucial role in maintaining the glycosylation enzymes across the Golgi cisternae. Our data suggest that GOLPH3 protein cooperates with Rab1 and the COG complex to regulate Golgi trafficking and glycosylation.

0Mutations in human COG7 and other COG genes cause distinct forms of inherited, autosomal recessive, congenital disorders of glycosylation (CDG) associated with multisystemic deficiencies. Clinical manifestations of COG-CDGs include psychomotor delay, epileptic seizures, general hypotonia and myopathy and failure to thrive. We have generated a Drosophila COG7-CDG model, which closely parallels the pathological characteristics of COG7-CDG patients, including pronounced neuromotor defects and altered N-glycome profiles. The Drosophila Cog7-CDG disease model, together with COG-CDG patients’ cells, offer unique opportunities to clarify the molecular mechanisms underlying COG-CDGs and help identify novel therapeutic strategies.