Signaling mechanisms underlying dendrite formation
Section snippets
Introduction: dendrite formation
Once a newly-born neuron is polarized, early dendrites will grow and branch out to initiate the formation of the dendritic arbor. Coincident with this process, filopodia extend from the new dendritic shafts. Some of these filopodia will become stabilized and generate club-like dendritic spines, depending on whether or not they encounter an appropriate axon and participate in synapse formation 1.•, 2.. Whereas both dendrites and axons extend with actin-based structures like growth cones leading
Multiple extrinsic cues regulate dendrite formation
Developing dendrites encounter a complex environment. They are surrounded by neighboring neurons and glia, and in many cases, afferent input axons arrive before or coincidentally with the initiation of dendritic growth. These early synaptic inputs expose the developing dendrites locally to neurotransmitters and more globally to action potentials; their importance is emphasized by numerous studies showing that a blockade of neurotransmission or global activity regulates developmental dendrite
Neuronal activity is a key signal for dendrite formation
A significant body of work [11] indicates that neurotransmitters and neural activity regulate both dendritic motility and net dendritic growth. In a compelling example of this, Lohmann et al. [12••] recently demonstrated that chick retinal ganglion cells displayed two patterns of spontaneous calcium increases in their dendrites, one global and the second involving neurotransmitter-mediated local ‘flashes’ of Ca2+. By differentially inhibiting these increases, they were able to show that
Neurotrophins and activity converge on the same signaling pathways to promote dendrite formation
It is well known that the neurotrophin family of growth factors regulates dendrite formation. A series of classic studies first established that target-derived NGF was essential for development and maintenance of sympathetic neuron dendrites [7], and these studies were then extended to the CNS in experiments on developing cortical slices [22]. More recently, Horch and Katz [23] overexpressed brain-derived neurotrophic factor (BDNF) in single cortical neurons in slices and demonstrated that
Axonal guidance molecules signal to direct and promote dendritic growth and guidance
One interesting (but perhaps not surprising) observation made over the past few years is that receptor–ligand systems that regulate axon guidance also modulate dendritic guidance and/or growth (Figure 2). The first report of this phenomenon was made by Polleux et al. [33] who demonstrated that semaphorin3A was a chemoattractant for cortical neuron dendrites at the same stage that it was a chemorepellant for cortical neuron axons. These authors provided evidence that soluble guanylate cyclase is
Some extrinsic cues actively signal to promote dendrite retraction
One of the conclusions discussed above is that if a newly formed dendrite is not stabilized by local activity, then it retracts. However, retraction is not just a default process; ligands have been identified that either inhibit dendritic growth and/or actively promote dendrite retraction. In particular, the Higgins laboratory has identified five ligands that negatively impact upon bone morphogenetic protein 7 (BMP7)-mediated sympathetic neuron dendrite growth 46., 47.•, 48.. Three were
Signaling dendrite formation: out on a Lim and ahead of the PAK while ROCKing and Rho-ling
A significant amount of previous work has implicated the Rho family in both axon growth 32.••, 51. and dendrite formation [52]. The Rho family of GTPases bind and hydrolyze guanosine nucleotides [53]. When in the GTP-bound state, Rho family proteins interact with a series of intracellular proteins that regulate the assembly and stability of the actin cytoskeleton. Rho proteins are regulated by enzymes that either enhance GTP binding (GEFs) and increase their activity or increase GTP hydrolysis
Conclusions
Our understanding of the signaling mechanisms that regulate dendrite formation has rapidly increased over the past two years. Multiple environmental cues, including neural activity, growth factors and guidance molecules converge to regulate formation and stabilization of dendritic shafts and spines both locally and distally at the nucleus. Neural activity and the neurotrophins converge on to the CaMKs and the MEK-ERK pathways to directly regulate the microtubule cytoskeleton, which is the major
Update
Recently, several reports have further elucidated the signaling pathways regulating dendritic morphogenesis. Of particular interest, one of the downstream targets of Rac1 and Cdc42 activity, JNK1 (jun-N-terminal kinase1), was found to be required for the maintenance of microtubule dynamics in the developing CNS [63•]. JNK1-/- mice exhibited a progressive loss of microtubules within dendrites, and MAP proteins, which are essential for dendrite assembly, were hypophosphorylated. In a second
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
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of special interest
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of outstanding interest
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