Biomedical subjects

Hwai-Jong Cheng

Publications and source records attributed to Hwai-Jong Cheng.

8 recordsLinked to original sources

PubMed2007

Axon pruning in the developing vertebrate hippocampus.

During early development of the central nervous system (CNS), there is an exuberant outgrowth of projections which later need to be refined to achieve precise connectivity. One widely used strategy for this refinement is axon pruning. Axon pruning has also been suggested to be involved in creating more diverse connection patterns between different species. An understanding of the mechanism of pruning, however, has been elusive in the CNS. Recent studies have focused on a stereotyped pruning event that occurs within the mossy fibers of the developing vertebrate hippocampus. In the following discussion, we will review the cellular and molecular factors that are known to regulate pruning in the hippocampus and highlight some advantages this system presents for future studies on pruning in the developing CNS.

Animals↗

PubMed2006

The Caenorhabditis elegans P21-activated kinases are differentially required for UNC-6/netrin-mediated commissural motor axon guidance.

P21 activated kinases (PAKs) are major downstream effectors of rac-related small GTPases that regulate various cellular processes. We have identified the new PAK gene max-2 in a screen for mutants disrupted in UNC-6/netrin-mediated commissural axon guidance. There are three Caenorhabditis elegans PAKs. We find that each C. elegans PAK represents a distinct group previously identified in other species. Here we examine their roles in the postembryonic migration of the P cell neuroblasts and the axon guidance of the ventral cord commissural motoneurons (VCCMNs). We find that the two PAKs, max-2 and pak-1, are redundantly required for P cell migration and function with UNC-73/Trio and the rac GTPases (CED-10 and MIG-2). During axon guidance of the VCCMNs, PAK-1 also acts with the rac GTPases, CED-10 and MIG-2, and is completely redundant with MAX-2. Interestingly, we find that unlike MAX-2 activity during P cell migration, for motoneuron axon guidance max-2 is also required in parallel to this PAK-1 pathway, independent of rac GTPase signaling. Finally, we provide evidence that MAX-2 functions downstream of the UNC-6/netrin receptor UNC-5 during axon repulsion and is an integral part of its signaling.

Amino Acid Sequence↗

PubMed2006

Axon pruning: an essential step underlying the developmental plasticity of neuronal connections.

Regressive events play a key role in modifying neural connectivity in early development. An important regressive event is the pruning of neuronal processes. Pruning is a strategy often used to selectively remove exuberant neuronal branches and connections in the immature nervous system to ensure the proper formation of functional circuitry. In the following review, we discuss our present understanding of the cellular and molecular mechanisms that regulate the pruning of axons during neuronal development as well as in neurological diseases. The evidence suggests that there are several similarities between the mechanisms that are involved in developmental axon pruning and axon elimination in disease. In summary, these findings provide researchers with a unique perspective on how developmental plasticity is achieved and how to develop strategies to treat complex neurological diseases.

Animals↗

PubMed2006

Axon pruning and synaptic development: how are they per-plexin?

During the development of the nervous system, neurons must first migrate to their appropriate locations and then send out axons to make connections. Various environmental cues guide these migrating neurons and growing axons. After axons reach their target regions, neuronal contacts are created through the formation of synapses. Because excess axonal branches and synaptic contacts are often formed during early development, they are pruned or eliminated at later stages to create specific neuronal connections. Several groups of ligand-receptor pairs have been identified to regulate each of these cellular events. Evidence also indicates that these same molecules may be used in multiple developmental processes. Here, we discuss semaphorins and plexins, the largest family of axon guidance ligand-receptor pairs. Because the roles of semaphorins in neuronal migration and axonal repulsion have been extensively reviewed, we will focus on plexin receptors. We will discuss how semaphorin signals are specifically passed through these receptors into cells and how plexins mediate their newly identified roles in axon pruning and synaptic development.

Animals↗

PubMed2005

Stereotyped axon pruning via plexin signaling is associated with synaptic complex elimination in the hippocampus.

Plexin signaling is required for stereotyped pruning of long axon collaterals in the vertebrate CNS; however, a cellular basis for plexins on stereotyped pruning has not been determined. Using quantitative electron microscopy and immunocytochemistry, we found that infrapyramidal mossy fiber axon collaterals form transient synaptic complexes with basal dendrites of CA3 pyramidal cells in the early postnatal mouse hippocampus. At later postnatal ages, these synaptic complexes stop maturing and are removed before stereotyped pruning by a mechanism that does not involve axon degeneration and glial cell engulfment. In knock-out mice that lack plexin-A3 signaling, the synaptic complexes continue to mature, and, as a result, the collaterals are not pruned. Thus, our results suggest that intact plexin-A3 signaling contributes to synaptic complex elimination, which is associated with stereotyped axon pruning.

Animals↗

PubMed2005

Differential requirement for Plexin-A3 and -A4 in mediating responses of sensory and sympathetic neurons to distinct class 3 Semaphorins.

The class 3 Semaphorins Sema3A and Sema3F are potent axonal repellents that cause repulsion by binding Neuropilin-1 and Neuropilin-2, respectively. Plexins are implicated as signaling coreceptors for the Neuropilins, but the identity of the Plexins that transduce Sema3A and Sema3F responses in vivo is uncertain. Here, we show that Plexin-A3 and -A4 are key determinants of these responses, through analysis of a Plexin-A3/Plexin-A4 double mutant mouse. Sensory and sympathetic neurons from the double mutant are insensitive to Sema3A and Sema3F in vitro, and defects in axonal projections in vivo correspond to those seen in Neuropilin-1 and -2 mutants. Interestingly, we found a differential requirement for these two Plexins: signaling via Neuropilin-1 is mediated principally by Plexin-A4, whereas signaling via Neuropilin-2 is mediated principally by Plexin-A3. Thus, Plexin-A3 and -A4 contribute to the specificity of axonal responses to class 3 Semaphorins.

Alleles↗

PubMed2005

A little nip and tuck: axon refinement during development and axonal injury.

While building the nervous system, regions of some developing axons are eliminated; this can also happen as a result of axonal injury. During development, many axon branches that are formed in excess of an organism's needs are fated for removal in a process called axon pruning. By contrast, when axons are injured the axon segment distal to the injury site is compartmentalized and eliminated. In both cases, the end result is similar -- a region of an axon is selected for removal. Recent evidence suggests that there are some similarities in the cellular and molecular mechanisms that regulate axon elimination in development and during axonal injury.

Animals↗

PubMed2003

Stereotyped pruning of long hippocampal axon branches triggered by retraction inducers of the semaphorin family.

Like naturally occurring neuronal cell death, stereotyped pruning of long axon branches to temporary targets is a widespread regressive phenomenon in the developing mammalian brain that helps sculpt the pattern of neuronal connections. The mechanisms controlling stereotyped pruning are, however, poorly understood. Here, we provide evidence that semaphorins, activating the Plexin-A3 receptor, function as retraction inducers to trigger-stereotyped pruning of specific hippocampal mossy fiber and pyramidal axon branches. Both pruning events are defective in Plexin-A3 mutants, reflecting a cell-autonomous requirement for Plexin-A3. The distribution of mRNAs for Sema3F and Sema3A makes them candidates for triggering the pruning. In vitro, hippocampal neurons respond to semaphorins by retracting axon branches. These results implicate semaphorins as retraction inducers controlling stereotyped pruning in the mammalian brain.

Animals↗