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Unpacking Reelin's Role in Neuronal Migration

22 February 2011. When neurons migrate by glia-independent means in developing mouse cortex, reelin signals help them reach their proper destination, according to a study published February 10 in Neuron. The study finds that the protein Disabled-1 (Dab1), a key part of the reelin pathway, is required for stages of migration that take place without the guidance of radial glial cells (RGCs). In contrast, glia-guided movement occurred normally without Dab1. Disrupting the glia-independent stages resulted in cell-layering defects just as severe as when reelin itself was lost, which suggests that these processes are critical for proper brain development. These findings offer clues to what goes awry in neurodevelopment disorders like schizophrenia.

Once a highly promising lead in schizophrenia pathology, the reelin gene (RELN) continues to produce findings of small effects on risk, leading some to suggest that it modifies features of the disorder (Wedenoja et al., 2010). In mice, reelin mutations disrupt neuron layering in the brain, leaving newborn neurons unable to migrate past their earlier-born predecessors as they should. Figuring out how this comes about has been a complicated endeavor, as reelin participates in an elaborate signaling pathway in multiple cell types. For example, reelin, located in the extracellular matrix, binds to receptors in RGCs and contributes to their shape. Because RGCs provide a kind of highway for migrating neurons, reelin-induced changes to RGC shape provide a widely accepted account for reelin-induced brain abnormalities.

But reelin also binds to receptors located on the migrating neurons themselves, triggering phosphorylation of Dab1, which then interacts with other molecules. Indeed, other studies have demonstrated a role for Dab1 within neurons during migration (Olson et al., 2006). To explore the contribution of this neuron-specific pathway to neuronal migration, lead researcher Ulrich Müller and colleagues at The Scripps Research Institute in San Diego, California, inactivated Dab1 in migrating neurons at key time points in development.

Trains, planes, and somal translocation
The timing of Dab1 inactivation matters because neurons born at different times use different modes of transportation to reach their final destinations. An early-born neuron headed for the deeper layers of the cortex not far from where neurons are born uses "somal translocation" to reach its destination: it puts out a leading process, fixes it in place, and then its cell body follows. A later-born neuron has farther to go, traveling past the early-born ones to form the more superficial layers of the cortex. It first uses multipolar migration, followed by locomotion along RGCs, and then somal translocation to reach its final position.

To inactivate Dab1 in newborn neurons, first authors Santos Franco and Isabel Martinez-Garay used a conditional knockout approach. They generated mice with Cre recombinase (CRE) splicing sites flanking one copy of the Dab1 gene. Next, they electroporated a neuron-specific vector containing CRE into mouse embryos in utero, resulting in the loss of Dab1 in newborn neurons, but not in glia.

When Dab1 was inactivated early on, the early-born neurons failed to reach their final destination. While 92 percent of control neurons made it into the cortical plate, only 4 percent of Dab1-inactivated neurons did. Instead, most of them were stuck below the subplate, closer to their birthplace. Although these mutant neurons seemed to extend processes successfully into the cortical plate, their cell bodies did not follow.

Inactivating Dab1 later, as neurons destined for superficial layers of the cortex were born, also perturbed migration. Though the multipolar and RGC migration portions of their journey appeared normal, these later-born neurons did not make it into the superficial layers of the cortical plate, as control neurons with normal Dab1 did. Time-lapse microscopy showed that Dab1-inactivated neurons traveled along RGCs normally, but in the final somal translocation phase of their journey, their cell bodies never followed their leading processes. This left later-born neurons in the wrong place in the brain.

Dab1's molecular machinery
Reelin affects both neurons and glia, but the researchers asked whether perturbing somal translocation by neurons alone could account for the reeler phenotype, in which reelin-deficient mice show abnormal brain development (see Katsuyama and Terashima, 2009). To explore this issue, the researchers generated mice that had a constitutive loss of Dab1 in migrating neurons but not in RGCs. Strikingly, the abnormal cell positioning in the brains of these mice was indistinguishable from that observed in reeler-like mice that had Dab1 inactivated in both glia and newborn neurons. This argues that somal translocation is not just fine-tuning a neuron's position, but rather is as critical to cell layering as glia-dependent migration.

Further experiments outlined the pathway of reelin signaling involved in somal translocation, ultimately connecting to cadherins. Reelin activation of Dab1 phosphorylation recruits PI3K and Crk/CrkL molecules, which in turn activate Limk1, a regulator of the leading process in migrating cells, and Akt1 and Rap1, which regulate cell adhesion. When the researchers inactivated each of these downstream players in early-born neurons that were migrating via somal translocation, they found migration defects only for Rap1 suppression. Similar to Dab1-inactivated neurons, the Rap1-deficient ones had leading processes that extended normally into the cortical plate, but their cell bodies did not follow. Rap1, in turn, acted through cadherins to maintain the leading process and/or help fix it in place upon reaching its destination. Interestingly, cadherin overexpression rescued Rap1-deficient migration anomalies, but could not correct the Dab1-deficient ones. This suggests that Dab1 acts through other molecules and may integrate several players involved in different aspects of somal translocation.

These findings not only illuminate how reelin acts, but they offer new insights into the multistep process of neuronal migration. Ultimately, disentangling the mechanisms behind the different parts of a neuron's journey in a developing brain will yield a deeper understanding of how brain development normally proceeds, and how it can be derailed, as suspected in schizophrenia.—Michele Solis.

Franco SJ, Martinez-Garay I, Gil-Sanz C, Harkins-Perry SR, Müller U. Reelin Regulates Cadherin Function via Dab1/Rap1 to Control Neuronal Migration and Lamination in the Neocortex. Neuron. 2011 Feb 10; 69:482-97. Abstract

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