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Lis1 Acts as Middleman for Actin and Microtubules

23 December 2005. If association hints at guilt, then researchers might make a case that Lis1 has a hand in the pathology of schizophrenia. This protein is in cahoots with some suspect characters, including DISC1 (see Brandon et al. 2005) and Reelin (see Assadi et al., 2003). A mutation of the former, full name Disrupted-In-Schizophrenia 1, is already on trial for causing the disease in an extended Scottish family with a high prevalence of neuropsychiatric disorders (see Millar et al., 2001 and SRF related news story), while postmortems showed that reelin is suspiciously reduced in the brains of people with schizophrenia or bipolar disorder with psychosis, but not unipolar depression (see Guidotti et al., 2000). But lest there be a rush to condemn Lis1, wouldn’t it be best to find out a little more about the protein? Elizabeth Ross and colleagues at Weill Medical College of Cornell University, New York, have done some detective work. Their findings, published online Dec 18 in Nature Neuroscience, suggest that Lis1 acts as the middleman between the cytoskeletal elements actin and microtubules. The data explain how the actin filaments interact with the tubulin cables to promote cell motility, a prerequisite for neuronal migration, as well as neuronal plasticity, two phenomena that are likely to be important in the pathology of schizophrenia and other disorders.

Lis1 was first identified because loss-of-function mutations in the gene cause a neurodevelopmental disease called lissencephaly (from the Greek, "lissos" meaning smooth and "enkephalos" meaning brain). In people born with this rare disease, neurons do not migrate properly and the cerebral cortex fails to fully develop, leaving a smooth cortical surface. Severe mental retardation, motor problems, and, often, death during infancy are the result. Researchers are currently trying to figure out why these mutations have such drastic consequences on cortical development. While it is known that Lis1 binds to microtubules, how this fits in with neuronal migration or lissencephaly has not been determined.

What has been clear for some time is that actin polymerization and depolymerization is a prerequisite for any cellular motility. Actin is the scaffold for the cytoskeleton, and for migration to take place, actin polymers must be disassembled at the trailing edge and reassembled at the leading edge of the moving cell. Ross and colleagues show that Lis1 promotes actin polymerization by stabilizing the active form of Cdc42, one of a number of small GTPases that regulate actin polymerization. When Cdc42 is turned on, it stimulates the enzyme that catalyzes the addition of actin monomers to growing actin chains, and so drives cell motility.

First author Stanislav Kholmanskikh and coworkers studied the role of Lis1 in migration of cerebellar granule cells. During their travels, these cells express the N-methyl-D-aspartate (NMDA) type of glutamate receptor (see Current Glutamate Hypothesis of schizophrenia by Moghaddam), and they can be persuaded to move on culture slides if given NMDA agonists such as glycine or serine. But the authors found that neurons from Lis1+/- mice responded poorly to serine, moving almost half as slowly as normal cells. They also found that extra Lis1 corrected this effect, but not if the cells also produced a dominant-negative form of Cdc42. In contrast, Lis1+/- cells producing a constitutively active form of Cdc42 migrated much faster than those without the GTPase. The results provided the researchers with the first solid evidence that Lis1-driven motility is related to activation of Cdc42.

The authors next investigated the activation process itself. One possibility was that it might involve another protein because active small GTPases are often protected by binding partners. In the leading edge of motile cell processes, for example, a protein called IQGAP stabilizes Cdc42. In fact, though IQGAP co-localizes with Cdc42/actin in growing neurites, Kholmanskikh and colleagues found that this is not the case in Lis+/- cells—in other words, the full complement of Lis1 is necessary to get IQGAP and Cdc42 together. This is where the microtubule connection comes in. Researchers previously showed that IQGAP forms a complex with a microtubule binding protein called cytoplasmic linker protein 170 (CLIP-170). Curiously, Lis1 also binds to CLIP-170 (see Coquelle et al., 2002), suggesting that all these proteins, Cdc42, IQGAP, CLIP-170 and Lis1 may exist in some sort of complex. Kholmanskikh and colleagues confirmed this by immunoprecipitation experiments.

In sum, these findings show that Lis1 is key in converting extracellular signals to intracellular motility and suggest how Lis1 mutations could prevent the proper migration of neurons to the cerebral cortex in lissencephaly. As for schizophrenia, it seems that there is not sufficient evidence to prosecute that case, yet. It is curious, however, that Lis1 forms a complex with DISC-1 and a protein called NUDEL (a.k.a., Ndel1). The genetic translocation in the DISC1 gene that is linked to schizophrenia produces DISC1 protein that cannot bind NUDEL, not to mention neuronal cells that cannot form neurites (see Ozeki et al., 2003). This latter observation is particularly intriguing because just like cell motility, neurite formation is dependent on rearrangement of the actin cytoskeleton.–Tom Fagan

Kholmanskikh SS, Koeller HB, Wynshaw-Boris A, Gomez T, Letourneau PC, Ross ME. Calcium-dependent interaction of Lis1 with IQGAP1 and Cdc42 promotes neuronal motility. Nat Neurosci. 2005 Dec 20. Abstract

Comments on News and Primary Papers
Primary Papers: Calcium-dependent interaction of Lis1 with IQGAP1 and Cdc42 promotes neuronal motility.

Comment by:  Shinji Hirotsune
Submitted 22 December 2005 Posted 22 December 2005

Lissencephaly is characterized by smooth cerebral surface,...  Read more

View all comments by Shinji Hirotsune

Primary Papers: Calcium-dependent interaction of Lis1 with IQGAP1 and Cdc42 promotes neuronal motility.

Comment by:  Nick Brandon (Disclosure)
Submitted 28 December 2005 Posted 28 December 2005

Lis1 is known to play a crucial role in neuronal migration...  Read more

View all comments by Nick Brandon

Primary Papers: Calcium-dependent interaction of Lis1 with IQGAP1 and Cdc42 promotes neuronal motility.

Comment by:  Barbara K. Lipska
Submitted 28 December 2005 Posted 28 December 2005

Subtle abnormalities in cortical axon growth, and synapse...  Read more

View all comments by Barbara K. Lipska

Comment by:  Akira Sawa, SRF Advisor
Submitted 12 January 2006 Posted 12 January 2006

I found the paper by Kholmanskikh and colleagues, which...  Read more

View all comments by Akira Sawa
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