Neuronal motility: When Lis is more

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The microtubule binding protein Lis1 stimulates neuronal motility by activating the RhoGTPase Cdc42 and promoting the formation of the CLIP-170/IQGAP-1 complex in response to Ca²⁺ influx.

Lis1 mutations impair neuronal migration causing a brain malformation known as lissencephaly. Previous studies have shown that Lis1 contributes to neuronal migration by regulating RhoGTPases as well as both microtubule and actin dynamics. The precise mechanism through which Lis1 signals to RhoGTPases is unclear. In Nature Neuroscience Kholmanskikh et al. now show that Lis1 can mediate the activation of Cdc42 and induce neuronal motility upon Ca²⁺ influx.

The authors found that D-serine, an NMDA receptor agonist, increases Ca²⁺ influx and enhances granule cell motility through a Cdc42-dependent pathway. In contrast, in granule cells from Lis1^+/- mice, D-serine did not stimulate neuronal motility despite triggering similar increases in intracellular Ca²⁺. As motility was restored by expressing either constitutively active Cdc42 or Lis1, the authors suggest that Lis1 regulates neuronal motility by mediating the Ca²⁺-dependent activation of Cdc42. In agreement with their hypothesis, D-serine-mediated Ca²⁺ influxes increase levels of F-actin and the number of filopodia in a Cdc42-dependent manner in wild-type neurons, but not in Lis^+/-cells.

To further examine the role of Lis1 in D-serine induced neuronal motility, the authors examined IQGAP1, a Cdc42-binding scaffold protein involved in Ca²⁺-dependent signaling to the cytoskeleton. Immunofluorescence experiments revealed that Lis1^+/- neurons have lower levels of IQGAP1, especially at the cell margins, compared to wild type. Previous studies have shown that both Lis1 and IQGAP1 bind to the microtubule plus-end binding protein CLIP-170. Co-precipitation experiments now show that D-serine facilitates the interaction between IQGAP1, CLIP-170 and active Cdc42 in a Lis1-dependent manner. Furthermore, RNAi-mediated knockdown of either IQGAP1 or CLIP-170 in wild type neurons blocked the effect of D-serine on neuronal motility. Because depletion of IQGAP1 or CLIP-170 did not lead to a further decrease in the motility of D-serine treated Lis1^+/- neurons, it is likely that Lis1, IQGAP1 and CLIP-170 function together as a complex to stimulate cell movement.

This study uncovers a role for Lis1 in Ca²⁺ signaling to the axonal cytoskeleton and the findings are particularly interesting in light of the role of the IQGAP1/CLIP-170 complex in microtubule capture at the plasma membrane in migrating fibroblasts. Examination of the microtubule network in migrating Lis^+/- cells should shed further light on the function of Lis1 in regulating actin-microtubule interactions.

Monica Hoyos-Flight
Cell Migration Gateway

References

Stanislav S. Kholmanskikh, Hajira B. Koeller, Anthony Wynshaw-Boris, Timothy Gomez, Paul C Letourneau & M. Elizabeth Ross. Calcium-dependent interaction of Lis1 with IQGAP1 and Cdc42 promotes neuronal motility. Nature Neuroscience 9, 50 – 57 (2005) | Article | PubMed |