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UCSF s McManus Discusses His New Lab and Mouse miRNA Knockout Consortium

Michael McManus
Assistant professor, microbiology/immunology
University of California, San Francisco

Name: Michael McManus

Position: Assistant professor, microbiology/immunology, University of California, San Francisco

Background: Postdoc, Massachusetts Institute of Technology — 2000-2004

PhD, cellular/molecular biology, University of Alabama at Birmingham — 2000

BS, horticultural sciences, Auburn University — 1991

After a stint as a postdoc in the lab of Alnylam Pharmaceuticals co-founder and MIT researcher Phillip Sharp, Michael McManus has landed at the University of California, San Francisco, where he is guiding his fledgling lab in its research into the biological processes of RNAi.

Recently, McManus spoke with RNAi News about his interest in the gene-silencing technology and his recent establishment of a consortium to develop knockout mouse models.

Let's start at the beginning with you getting into RNAi. You were a postdoc in Phil Sharp's lab [at MIT]. Is that where it started for you?

That's exactly where RNAi started for me. But I initially became interested in small RNAs as a graduate student. In graduate school I worked in Steve Hajduk's laboratory studying RNA editing in trypanosomes, on a type of editing called insertional-deletional editing. It's where small RNAs guide RNA editing events by specifying where to add uridine nucleotides into an RNA, and where to remove them, and how many to remove, and how many to add; these process are all guided by small RNAs. The breadth of activities of small RNAs is great and certainly extends beyond RNAi.

To put things in relation to each other, when was that as opposed to when you started working in the Sharp lab?

I finished my PhD in late 2000 and joined the Sharp lab [later the same year]. So I became interested in RNA interference during my time as a student. At the time, RNAi was being used in worms and was starting to be used in trypanosomes, and I just knew there was going to be some cool and interesting biology present in the mammalian system. That's when I decided to move my focus in small RNAs in mammals.

Could you talk a little about how you set up your lab and the kinds of things you're working on … now that you're on the other coast?

One of the things I learned at MIT was how to develop mouse models. That training has allowed me to develop a laboratory centered around the use of mouse models, and we are exploring the functional biology of the RNA interference pathway in mouse models.

Specifically, we make transgenic mice with knockouts for different components of the RNA interference pathway: Dicer, Slicer, Drosha, et cetera. We've made mouse knockouts for all of these genes and we are currently characterizing these models.

So what you're concerned with is figuring out how the RNAi pathway works — the basics of the whole thing?

Exactly — especially in an in vivo setting.

Can you give a little insight into some recent findings?

We've been exploring the role of Dicer in various tissue contexts in the mouse. We recently published a paper in [The Proceedings of the National Academy of Sciences] co-authored with Brian Harfe and Cliff Tabin's group at the University of Florida [College of Medicine describing experiments in which] we ablated Dicer in the limbs of a mouse in order to study the effects of Dicer depletion in a developmental setting. We discovered that … remarkably you can still develop limbs in the mouse, although the limbs are morphologically disturbed.

We are questioning whether Dicer is going to be involved in pathways that regard patterning. Instead, it could be involved in processes of morphology, for example. We're continuing to explore this aspect of Dicer's role in cells in the mouse by ablating Dicer in other tissues in the developing limb and studying the cellular and molecular nature of the phenotypes.

What about some other areas of research … and other questions you're looking to answer?

We are doing these mouse models, so we're excited to figure out the roles of these small RNAs in cells. And the Dicer system is a great one in which to get an overview for the role of RNAi-related processes in cells, but it really is a low-resolution model. In other words, we're ablating probably all the microRNAs expressed in a given cell, and perhaps affecting other pathways that relate to double-stranded RNA. So we're turning our attention to developing more specific mouse knockouts for microRNAs and I'm heading up a consortium now with a number of different investigators in which we're knocking out hundreds of microRNAs in the mouse.

This consortium, is it based at the University of California?

It's based here, but we have consortium members across the United States. Because this is a very large-scale undertaking, it involves the expertise of a number of different individuals.

When was this established?

Probably about six months ago. It's still at the very early stages right now.

When you work in the mouse field, you find that experiments take you a lot longer than if you were working in single cells in culture. So it's going to be some time before we see much — it's still too early to say anything.

Has it been given a name?

We're calling it the Mouse microRNA Knockout Consortium, imaginative as we are.

We hope that these mice will provide useful models for interrogating the specific functions for microRNAs in development and, more importantly, in disease.

If other researchers want to get information about the consortium, is there a website they can go to?

Not yet, but we hope to put one up so that we can have investigators visit it, potentially get information about the mice, access the mice, et cetera.

Who were some of the key members in putting the consortium together?

I established the consortium. I recognized there was a need and decided to fill it. Like any science these days, collaborations are key for moving things forward in a reasonable time frame.

About how many members do you have at this point?

Right now … we have five members including myself. It might be premature [to disclose the members]. I'm not sure how much we want to advertise this at the moment because it's still early. We might be adding additional members, as well, since we are interested in partnering with industry.

Is this the kind of thing that you'd hope to get industry involved with?

We are. We are seeking industry funding to support some of our efforts. Making mice is very expensive, even though we've developed some high-throughput approaches to trim down the cost so that we can do it cheaply and quickly.

Have you gotten [feedback] from people about these models yet? As you say, they're expensive and can be difficult to do. People must be interested …

We're quite good at creating transgenic models. Right now, we're in discussions with various companies, but it's too early to comment much on that.

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