Sticky situations: recent advances in control of cell adhesion during neuronal migration
Highlights
► A major challenge to the neuronal migration field has been to elucidate adhesive control mechanisms required for migration target recognition and pathway selection. ► Endocytosis related mechanisms help retrieve adhesion receptors like Astrotactin2, Integrin and N-Cadherin, from the neuronal cell surface. ► Cell polarity proteins; like Rap1A and the PAR complex facilitate adhesion receptor recruitment to the neuronal cells surface controlling events like germinal zone exit, tangential to radial migration switch, multipolar transition and terminal somal translocation.
Introduction
Until the mid-1990s, adhesive mechanisms were the focus of efforts to understand the recognition and pathway-specific migration of neurons in the developing brain [1, 2, 3]. Early classical ultrastructural electron microscopy [4] and correlated high-resolution time-lapse electron microscopy [5] provided tantalizing clues to the exquisite specificity of neuronal adhesion to migration substrates and the potential dynamic remodeling of neuron–glial junctions. The molecular cloning of adhesion receptors identified molecules that putatively mediate neuron–neuron or neuron–glial adhesive events [6, 7, 8, 9, 10, 11]. Moreover, gene targeting in the mouse showed that many of these molecules play key roles in migratory events in vivo during assembly of the brain's cortical regions [12, 13, 14, 15, 16, 17]. However, it proved difficult to elucidate the molecular mechanisms that control neuronal adhesive affinity or avidity by altering levels or types of adhesion molecules expressed at the cell surface. For example, the mechanisms proposed to alter cell surface adhesion receptor strength, such as carbohydrate modification of N-CAM [18, 19, 20, 21] or transcription of ASTN1 mRNA during cerebellar granule neuron (CGN) differentiation [3, 7], take much longer than the seconds to minutes needed to remodel neuronal junctions demonstrated by time-lapse/electron microscopy for neuron migrating along glial fibers [5]. Moreover, few tools other than antibodies were available to observe the molecular components of junctions and manipulate adhesion receptor function.
Great progress in our ability to examine the molecular mechanisms controlling cell adhesion during neuronal migration have resulted from striking advances in ex vivo and in vivo manipulation of neurons, cell biology tools to alter receptor function, small-molecule inhibitors, and advanced time-lapse imaging. These tools have not only confirmed some early ultrastructure-based predictions about vesicle recycling and exocytosis but also implicated conserved polarity signaling pathways in adhesion receptor trafficking, linked conserved adhesion pathways to extrinsic signaling molecules like Reelin, and, for the first time, allowed direct visualization of adhesion receptor trafficking at the neuronal cell surface.
Section snippets
Endocytosis and neuronal adhesion
Adhesion receptor trafficking has long been implicated in migration of motile cells, such as fibroblasts and leukocytes [22, 23, 24, 25, 26]. Insertion of new adhesion receptors forward of the cell body is thought to generate traction that pulls cell components forward, while removal of adhesive elements in the rear may facilitate forward translocation. Thus, the balance between exocytosis and endocytosis and the site of adhesion receptor insertion and retrieval are major factors in the
Polarity signaling and neuronal adhesion
While the endocytosis studies described above provide some mechanistic insight into retrieval of adhesion receptors from the neuron surface, new reports suggest that conserved polarity signaling molecules, such as the partitioning defective (PAR) complex or the Rap1 GTPase regulate the extent of cell-surface adhesion receptor recruitment (Figure 1c). Moreover, fine-tuning of adhesion receptor function through polarity signaling molecules provides a new mechanism for the control of GZ exit,
Neuronal adhesion dynamics
In general models of cell motility, adhesion formation and disassembly drive migration by regulating how a cell binds to actomyosin and uses it to pull against migration substrates [66, 67]. While various adhesion molecules are known to mediate binding of neurons to their glial or nonglial guides [68, 69, 12], we lack the tools to examine the basic features of neuronal adhesion in living cells in a dynamic, high-throughput fashion.
Two recent studies using fluorescence-labeled adhesion molecules
Conclusions
Over the past two decades, much progress has been made in identifying molecules that mediate the interaction of migrating neurons with glial or neuronal substrates on their journey to a final laminar position. Clearly, regulation of the affinity or avidity of the array of cell-surface adhesion receptors is crucial to guide a neuron's migration path. An important challenge facing this field is to identify how cell-extrinsic cues cooperate with both the genetic programs controlling neuronal
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
I thank Niraj Trivedi and Danielle Howell for critically reading the manuscript and helpful discussion. Sharon Naron provided expert editorial support. This study was funded by the American Lebanese Syrian Associated Charities (ALSAC) and by Grant Number 1R01NS066936 from the National Institute of Neurological Disorders (NINDS). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NINDS or the NIH.
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