The American Society for Cell Biology - www.ascb.org 46th annual Meeting 9-13th December 2006 San Diego Convention Center
Cell Biology and Lowe Syndrome (room 14B)
Robert L. Nussbaum University of California San Francisco
Lowe Syndrome is an x-linked human disorder affecting mental development, lens of the eye, and kidney. The purpose of the meeting was to bring together
cell biologists to share ideas about future research directions for understanding the connection between the biochemical defect and the disease on the tissue and organ level.
On December 9th 2006, a group of researchers gathered in a satellite meeting at the 46th American Society of Cell Biology (ASCB) meeting in San Diego, to present recent findings on the Oculocerebrorenal Syndrome of Lowe, or Lowe syndrome. This satellite meeting, sponsored by the Lowe syndrome Trust (UK) and given under the auspices of the largest and most prestigious professional scientific society for cell biology in the world, the ASCB, was well attended by 40-50 cell biologists, including a number of young investigators from outside the Lowe syndrome field who were attending the ASCB meeting.
Encouragingly, it appears there is major progress in our understanding of the normal function of the protein (ocrl1) encoded by the OCRL gene, with more researchers beginning to study the problem and making exciting new discoveries. Dr Yuxin Mao, from Dr Pietro De Camilli’s group at Yale University, typified this by describing a number of key findings including the determination of the three-dimensional structure of the carboxy-terminal region of ocrl1, which provides a molecular explanation for how it can dock onto membranes and recognise its substrates. Dr Mao also found that ocrl1 localised to clathrin-coated pits, which are specialized cellular structures that mediate endocytosis at the cell surface, and interestingly found an enrichment of the protein at the apical side of kidney tubule cells, where absorption of material occurs. Together, these findings suggest that apical endocytosis may be defective in Lowe syndrome, resulting in a failure to properly absorb material in the kidney. Another interesting observation presented by Dr Mao was the binding of ocrl1 to a protein called APPL, which is involved in generating intracellular signals at endosomes, suggesting a role for ocrl1 in signalling from endocytic intermediates.
Analysis of ocrl1 in other kidney cell based model systems suggested roles for the protein in other membrane traffic pathways in the cell. Dr Chris Guerriero from the lab of Dr Ora Weisz in Pittsburgh reported a role for ocrl1 in regulating polarised delivery of certain proteins to the apical side of kidney cells in a mechanism involving changes in actin dynamics. In another interesting presentation, Dr Alex Ungewickell from the lab of Dr Philip Majerus at Washington University of St Louis described a novel hypothesis in which it was proposed ocrl1 regulates the polarised delivery of an ion transporter to the opposite side of kidney cells, where it is required to maintain kidney ion balance and uptake processes. Initial findings suggested that ocrl1 might control the polarised distribution of this important protein. Findings presented by Dr Martin Lowe from Manchester University pointed at a role in yet another membrane traffic step in the cell, namely transport from the endosomes to the Golgi apparatus. At present it is not clear to what extent ocrl1 regulates the various membrane flow pathways in a cell or how these pathways contribute to the pathophysiology of Lowe syndrome, but these initial studies lay the groundwork for future advances in this area.
It has emerged in recent years that lipids can be transported between membrane compartments via direct contact sites, and that this is important in the synthesis of different lipid types, including sphingolipids, which have important functions at the cell surface. Dr Antonella De Matteis from the Mario Negri Institute at Santa Maria Imbaro in Italy described a novel role for ocrl1 in the production of sphingolipids at the Golgi apparatus, pointing to yet another avenue for future research into Lowe syndrome.
Analysis of yeast proteins related to ocrl1 has also proven informative in terms of understanding the basic biology underlying Lowe syndrome, as exemplified by the elegant work presented by Dr Christopher Stefan, from Scott Emr’s group in San Diego and Prof. Jeremy Thorner from the University of California in Berkeley. These talks nicely illustrated how a combination of yeast genetics and cell biology can lead the way in studying the mechanisms by which lipid metabolism regulates different aspects of cell behaviour, including endocytosis and cell migration, two processes which are relevant to our understanding of Lowe syndrome.
Despite not being the focus of this meeting, there have been a number of studies into the genetic basis of Lowe syndrome. It has been known for years that the severity of the disease can vary dramatically, even in patients with identical mutations in the gene encoding ocrl1. Furthermore, recent studies on Dent disease have revealed that patients with this disorder, which shares only some of the renal findings in Lowe syndrome, have mutations in ocrl1. These findings suggest there are other genes that influence the range and severity of Lower syndrome symptoms, so-called “genetic modifiers”. Dr Sharon Suchy of the NHGRI at Bethesda has undertaken a “gene expression chip” based approach to identify other genes that are more or less highly expressed in Lowe syndrome and Dent’s disease patients and to try and correlate these with differing physical symptoms. Initial studies suggest a link with the Wnt signalling pathway, which is important for establishing cell polarity during early development. Considering the tissues affected in Lowe syndrome are polarised, this is an exciting finding, and one that merits further investigation.
It is worth emphasizing the role played by the voluntary parent organizations in promoting research in Lowe syndrome. Research into this disorder is gathering momentum, which has a lot to do with the interest and curiosity of the researchers involved, but also the dedication, encouragement and financial support offered by organisations such as the UK Lowe Syndrome Trust and the US Lowe Syndrome Association. For example, The Lowe Syndrome Trust, under the leadership of Lorraine Thomas, helped organise this meeting together with Dr. Robert Nussbaum, the original discoverer of the ocrl1 protein, and has supported a number of research projects in Lowe Syndrome, including work in Dr. Nussbaum’s laboratory. As another example, two of the other eminent speakers at the meeting, Dr. Thorner and Dr. De Matteis, have received funding for research from the Lowe Syndrome Association.
The meeting in San Diego was stimulating from a cell biological perspective, but also importantly, encouraging from the broader view of trying to understand and treat Lowe syndrome. Let us hope the findings presented at the meeting pave the way for further breakthroughs in Lowe syndrome research that ultimately transmit to the clinic.
Dr Martin Lowe
University of Manchester, UK.
Dr. Robert Nussbaum
University of California, San Francisco
January 29th, 2007.
Speakers:
Introduction and Statement of the Problem. Robert Nussbaum, University of California, San Francisco.
Inositol 5-phosphatases in the Endocytic Pathway. Pietro de Camilli, Yale University
Phosphoinositide Lipid Signalling in the Regulation of Membrane Trafficking. Scott Emr, University of California, San Diego
A search for Genetic Modifier of OCRL1 Deficiency. Sharon Suchy, National Genome Research Institute/NIH
Phosphatidylinositols and the Regulation of Apical Membrane Traffic in Renal Epithelial Cells,. Ora Weisz, University of Pittsburgh
OCRL1 and Membrane Traffic at the Endosome/Golgi Interface. Martin Lowe, University of Manchester, UK
The Phosphoinositides and the Golgi Complex. Maria Antoinetta de Matteis, Santa Maria Imbaro, Italy
Signal-induced Anisotrophy in Plasma Membrane PtdIns (4.5)P2 Distribution. Jeremy Thorner, University of California, Berkeley
A Hypothesis: Does Abnormal Trafficking of NBC1 in Lowe Syndrome explain its clinical presentation? Alex Ungewickell, Washington University in St Louis.