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Annotation

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 ; PubMed Abstract

Comments on Paper and Primary News
Comment by:  Shinji Hirotsune
Submitted 22 December 2005 Posted 22 December 2005

Lissencephaly is characterized by smooth cerebral surface, thick cortex, and dilated lateral ventricles due to incomplete neuronal migration. Lis1 is one of the major mutated genes linked to this disease. Recent reports support Lis1 as an important regulator of cytoplasmic dynein heavy chain and microtubule organization with Ndel1, which is a binding partner of Lis1.

For neuronal migration, proper regulation of the cytoskeleton including microtubules and actin filaments is also essential (reviewed by Luo, 2000 and Noritake et al., 2005). Although accumulating evidence suggested the presence of a cross-talk mechanism between these two cytoskeletal elements, the precise mechanism remained to be elucidated. The paper from Rossís group has shed light on this important paradigm. They demonstrated that Lis1 is a key molecule which promotes Cdc42 activation through interaction with the calcium-sensitive GTPase scaffolding...  Read more


View all comments by Shinji Hirotsune

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

Lis1 is known to play a crucial role in neuronal migration and neurogenesis. This is shown most dramatically by human lissencephaly where mutations in Lis1 give rise to a reduction in the convolutions of the cerebral cortex and disrupted cortical layering (Dobyns, 1989). This current paper builds on earlier work showing that the neuronal migration deficits in Lis1+/- animals is due in part to dysregulation of small GTPases such as Cdc42 and rac1 and consequent disruption of the actin cytoskeleton. The new manuscript details the molecular mechanism for the observed deficiency by revealing that Lis1 activates small GTPases through interacting with a GTPase scaffolding protein known as IQGAP1 in a calcium-dependent manner. Understanding the normal function of Lis1 could be important to allow us to understand the root causes of not only lissencephaly but also other diseases with common deficits. This includes schizophrenia, where postmortem studies show that schizophrenics have neuroanatomical...  Read more


View all comments by Nick Brandon

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

Subtle abnormalities in cortical axon growth, and synapse formation have been long posited in schizophrenia, although the mechanisms of these deficits are still unclear (Lewis et al., 2003). Recently, with the growing evidence for a number of putative susceptibility genes, it was speculated that the genes may all converge functionally upon schizophrenia risk via an influence upon synaptic plasticity and the development and stabilization of cortical microcircuitry (Harrison and Weinberger, 2005).

The paper by Kholmanskikh and colleagues provides strong evidence that Lis1 is the transduction molecule linking extracellular Ca2+ activated motility signals with intracellular regulation of the cytoskeleton. Insufficient Lis1 destabilizes actin/microtubule complexes and thus disrupts cell architecture and neurite outgrowth. In other words, this paper provides data that Lis1, based on its biological role, might be a potential...  Read more


View all comments by Barbara K. Lipska

Primary News: Lis1 Acts as Middleman for Actin and Microtubules

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

I found the paper by Kholmanskikh and colleagues, which proposes a novel role for LIS1 in neuronal motility by bridging calcium signaling to Cdc42, of great interest for schizophrenia research. LIS1 was originally identified as the causative gene for lissencephaly, but cascades that include LIS1 may have implications for schizophrenia. Several groups, including ours, have reported that a candidate gene product for schizophrenia, DISC1, forms a protein complex with LIS1 (Brandon et al., 2004; Kamiya et al., 2005).

My collaborators, Brian Kirkpatrick and Rosy Roberts, have observed and presented data that DISC1 immunoreactivity is enriched in some (but not all) of the postsynaptic densities, where Rho-family GTPases, such as Cdc42, also occur and regulate synaptic functions (Society for Neuroscience Meeting, 2004). Many of us agree that schizophrenia is, at least in part, a disorder of synapses. Taken all...  Read more


View all comments by Akira Sawa
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