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Taniguchi, H. A constitutively active form of RhoA inhibits the growth of minor neurite processes in hippocampal neurons Threadgill et al. Conditional knockout of RhoA in the midbrain results in the disruption of apical adherens junctions, hyper-proliferation of neural progenitors and massive dysplasia of the brain Katayama et al.
However, the role of RhoA in neuronal polarization in vivo remains to be elucidated. Therefore, the activity of RhoA is important for the establishment of neuronal polarity.
Interestingly, RhoA activity is higher in the growth cones of minor neurites of polarized neurons than in the growing axon Gonzalez-Billault et al. Neuronal polarization is driven by cytoskeletal organization, primarily through microtubule and actin dynamics Arimura and Kaibuchi, ; Barnes and Polleux, The stabilization of microtubules is crucial for the axon specification in vitro Bradke and Dotti, ; Witte and Bradke, Tau protects microtubules from the microtubule-serving proteins Witte and Bradke, In contrast to microtubules, actin filaments are more unstable and dynamic in the growing axon than the growth cones of minor neurites in vitro Bradke and Dotti, ; Witte and Bradke, The destabilization of actin filaments by severing proteins such as cofilin allows microtubules to penetrate into the growth cone, thereby leading to axon specification Bradke and Dotti, ; Flynn et al.
Conversely, myosin II and profilin IIa stabilize actin filaments at the minor neurites to prevent the formation of multiple axons through interfering with the penetration of microtubules Kollins et al. Thus, the coordinated regulation of microtubules and actin filaments plays a crucial role in neuronal polarization.
These positive regulators are continuously activated within one minor neurite and thereby induce axon initiation via multiple downstream routes that impinge on cytoskeletal and intracellular trafficking dynamics Arimura and Kaibuchi, ; Takano et al. However, the molecular mechanism of global inhibition remains a mystery. Rho kinase phosphorylates Par3 and in turn disrupts the Par complex, thereby abrogating Rac1 activation Nakayama et al. Local elevation of cAMP in a neurite of the unpolarized neuron also might generate a long-range negative-feedback signaling that results in the reduction of cAMP in all other neurites Shelly et al.
Recently, a global inhibitory regulatory mechanism has been proposed: because growth-promoting factors are limited, a local accumulation of these factors in the nascent axon could deplete them in other minor neurites without a long-range negative-feedback signal Inagaki et al. According to these paradigms, dendrite specification could be a default pathway in the absence of axon specification in cultured neurons. In the developing cortex, however, one of the minor neurites of a MP cell develops into the leading process.
Additional dendrite-specific processes caused by environmental cues might be required for neuronal polarization in vivo as described above. The elucidation of the molecular mechanisms inducing global inhibition to determine dendrite specification is a crucial issue in neuronal polarity research. The establishment of neuronal polarization is essential for establishing proper neuronal circuits and functions. A large number of studies both in vitro and in vivo have uncovered a complicated signaling network regulating neuronal polarity Arimura and Kaibuchi, ; Barnes and Polleux, ; Tahirovic and Bradke, However, despite intensive study, it is still unclear how neurons generate only one axon and multiple dendrites.
In particular, the molecular mechanisms of global inhibition underlying the maintenance of neuronal polarity remain elusive, and there may be unknown molecular machinery functioning to prevent the formation of multiple axons and in turn to induce dendritic outgrowth. One reason for this major gap in our knowledge is the lack of suitable methodologies for investigating the spatiotemporal regulation of the signaling molecules responsible for negative-feedback signaling.
Future challenges will entail exploring these issues using advances in imaging technology, genetic model systems and innovative experimental approaches. Despite our incomplete understanding, the molecular mechanisms identified thus far seem to be widely used and evolutionarily conserved Solecki et al. Therefore, our understanding of the molecular mechanisms leading to neuronal polarization is likely to provide new insights into the development of brain circuitry.
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Advanced Search. User Tools. Sign in. Skip Nav Destination Article Navigation. Close mobile search navigation Article navigation. Volume , Issue Previous Article Next Article. Article contents. Overview of neuronal polarization in vitro and in vivo. Signaling pathways involved in neuronal polarization. Cytoskeletal organization. Local activation and global inhibition for neuronal polarization. Development at a Glance. Article Navigation. Neuronal polarization Tetsuya Takano , Tetsuya Takano.
Department of Cell Pharmacology. This site. Google Scholar. Chundi Xu , Chundi Xu. The physical mechanism responsible for such length-related differentiation has not been established. Here, we present a model of neuronal polarization based upon the existence of a "determinant chemical' whose concentration at the neurite tips influences the growth rate of the neurite.
Over an extended parameter range the equations describing the formation, transport, and consumption of this chemical and the resulting neurite growth undergo a winner-take-all instability, yielding rapid growth of one neurite the axon and diminished growth of all others.
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