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Semaphorin signaling in vertebrate neural circuit assembly.

Yoshida Y - Front Mol Neurosci (2012)

Bottom Line: The major semaphorin receptors are plexins and neuropilins, however other receptors and co-receptors also mediate signaling by semaphorins.Upon semaphorin binding to their receptors, downstream signaling molecules transduce this event within cells to mediate further events, including alteration of microtubule and actin cytoskeletal dynamics.Here, I review recent studies on semaphorin signaling in vertebrate neural circuit assembly, with the goal of highlighting how this diverse family of cues and receptors imparts exquisite specificity to neural complex connectivity.

View Article: PubMed Central - PubMed

Affiliation: Division of Developmental Biology, Cincinnati Children's Hospital Medical Center Cincinnati, OH, USA.

ABSTRACT
Neural circuit formation requires the coordination of many complex developmental processes. First, neurons project axons over long distances to find their final targets and then establish appropriate connectivity essential for the formation of neuronal circuitry. Growth cones, the leading edges of axons, navigate by interacting with a variety of attractive and repulsive axon guidance cues along their trajectories and at final target regions. In addition to guidance of axons, neuronal polarization, neuronal migration, and dendrite development must be precisely regulated during development to establish proper neural circuitry. Semaphorins consist of a large protein family, which includes secreted and cell surface proteins, and they play important roles in many steps of neural circuit formation. The major semaphorin receptors are plexins and neuropilins, however other receptors and co-receptors also mediate signaling by semaphorins. Upon semaphorin binding to their receptors, downstream signaling molecules transduce this event within cells to mediate further events, including alteration of microtubule and actin cytoskeletal dynamics. Here, I review recent studies on semaphorin signaling in vertebrate neural circuit assembly, with the goal of highlighting how this diverse family of cues and receptors imparts exquisite specificity to neural complex connectivity.

No MeSH data available.


Class 5 and class 6 transmembrane semaphorin signaling through plexinAs governs laminar targeting of inner retinal neuron subtypes. (A) Sema6A and PlexA4 show complementary protein expression in the ON and OFF layers of the inner plexiform layer, and this repulsive signaling confines neurite extension of dopaminergic amacrine cells (TH+) within the S1 sublamina in wild-type mice. In Sema6A or PlexA4 mutant mice, dopaminergic amacrine cells extend their aberrant processes to the S4/S5 sublaminae. (B) During early postnatal retinal development, Sema5A/5B and PlexA1/A3 expressions are found in a complementary pattern in the retina. Loss of Sema5A/5B or plexA1/A3 results in neurite mistargeting of multiple inner retinal neuron subtypes into the outer retina.
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Figure 3: Class 5 and class 6 transmembrane semaphorin signaling through plexinAs governs laminar targeting of inner retinal neuron subtypes. (A) Sema6A and PlexA4 show complementary protein expression in the ON and OFF layers of the inner plexiform layer, and this repulsive signaling confines neurite extension of dopaminergic amacrine cells (TH+) within the S1 sublamina in wild-type mice. In Sema6A or PlexA4 mutant mice, dopaminergic amacrine cells extend their aberrant processes to the S4/S5 sublaminae. (B) During early postnatal retinal development, Sema5A/5B and PlexA1/A3 expressions are found in a complementary pattern in the retina. Loss of Sema5A/5B or plexA1/A3 results in neurite mistargeting of multiple inner retinal neuron subtypes into the outer retina.

Mentions: Specific patterns of synaptic connections in many regions of the nervous system are organized within laminae. One of the most best studied laminar structures found in the vertebrate nervous system is the retina. In the vertebrate retina, distinct subtypes of RGCs, amacrine cells (ACs), and bipolar cells (BCs) make synaptic connections within specific synaptic plexus of the inner plexiform layer (IPL), a laminar structure that is conventionally divided into 5–10 sublaminae (reviewed in Wässle, 2004; Sanes and Zipursky, 2010). Recently, two studies using mouse genetics demonstrate that different classes of transmembrane semaphorins regulate select aspects of retinal lamination and function in the mammalian retina (Matsuoka et al., 2011a,b). Though previous reports showed that certain semaphorins, Npns, and plexins are expressed in the developing mammalian retina (Leighton et al., 2001; de Winter et al., 2004), how semaphorin signaling regulates retinal development and circuit assembly was not known. Matsuoka et al. (2011a) investigated the in vivo roles of semaphorin signaling components in retinal development by analyzing mice that lack each plexin and neuropilin. Through an extensive phenotypic analysis of the mutant mice, the authors found that dopaminergic ACs and M1-type melanopsin intrinsically photosensitive retinal ganglion cells (ipRGCs), both of which exhibit neurite stratification predominantly within the S1 sublamina of the IPL in wild-type retinas, extend aberrant processes into S4/S5 in PlexA4-deficient retina (Matsuoka et al., 2011a; Figure 3A). Since PlexA4 is expressed by dopaminergic ACs but not by M1-type ipRGCs, this result suggests that the M1-type ipRGC dendritic stratification deficit within the IPL of PlexA4-deficient retina is likely a secondary consequence of defects in AC stratification within the IPL of the PlexA4-deficient retina, providing further support for ACs directing RGC dendritic stratification in the IPL (Stacy and Wong, 2003; Mumm et al., 2006; Matsuoka et al., 2011a). Sema6A and its receptor PlexA4 exhibit complementary protein expression patterns within the IPL, suggesting that Sema6A functions as a repulsive barrier within the IPL for neuronal processes expressing PlexA4 (Matsuoka et al., 2011a). Sema6A mutants show the same defects in neurite stratification within the IPL as observed in PlexA4 mutants (Matsuoka et al., 2011a; Figure 3A). Thus, these results show that Sema6A is a functional ligand for PlexA4, required for regulating select retinal neurite stratification in vivo (Matsuoka et al., 2011a; Figure 3A).


Semaphorin signaling in vertebrate neural circuit assembly.

Yoshida Y - Front Mol Neurosci (2012)

Class 5 and class 6 transmembrane semaphorin signaling through plexinAs governs laminar targeting of inner retinal neuron subtypes. (A) Sema6A and PlexA4 show complementary protein expression in the ON and OFF layers of the inner plexiform layer, and this repulsive signaling confines neurite extension of dopaminergic amacrine cells (TH+) within the S1 sublamina in wild-type mice. In Sema6A or PlexA4 mutant mice, dopaminergic amacrine cells extend their aberrant processes to the S4/S5 sublaminae. (B) During early postnatal retinal development, Sema5A/5B and PlexA1/A3 expressions are found in a complementary pattern in the retina. Loss of Sema5A/5B or plexA1/A3 results in neurite mistargeting of multiple inner retinal neuron subtypes into the outer retina.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Figure 3: Class 5 and class 6 transmembrane semaphorin signaling through plexinAs governs laminar targeting of inner retinal neuron subtypes. (A) Sema6A and PlexA4 show complementary protein expression in the ON and OFF layers of the inner plexiform layer, and this repulsive signaling confines neurite extension of dopaminergic amacrine cells (TH+) within the S1 sublamina in wild-type mice. In Sema6A or PlexA4 mutant mice, dopaminergic amacrine cells extend their aberrant processes to the S4/S5 sublaminae. (B) During early postnatal retinal development, Sema5A/5B and PlexA1/A3 expressions are found in a complementary pattern in the retina. Loss of Sema5A/5B or plexA1/A3 results in neurite mistargeting of multiple inner retinal neuron subtypes into the outer retina.
Mentions: Specific patterns of synaptic connections in many regions of the nervous system are organized within laminae. One of the most best studied laminar structures found in the vertebrate nervous system is the retina. In the vertebrate retina, distinct subtypes of RGCs, amacrine cells (ACs), and bipolar cells (BCs) make synaptic connections within specific synaptic plexus of the inner plexiform layer (IPL), a laminar structure that is conventionally divided into 5–10 sublaminae (reviewed in Wässle, 2004; Sanes and Zipursky, 2010). Recently, two studies using mouse genetics demonstrate that different classes of transmembrane semaphorins regulate select aspects of retinal lamination and function in the mammalian retina (Matsuoka et al., 2011a,b). Though previous reports showed that certain semaphorins, Npns, and plexins are expressed in the developing mammalian retina (Leighton et al., 2001; de Winter et al., 2004), how semaphorin signaling regulates retinal development and circuit assembly was not known. Matsuoka et al. (2011a) investigated the in vivo roles of semaphorin signaling components in retinal development by analyzing mice that lack each plexin and neuropilin. Through an extensive phenotypic analysis of the mutant mice, the authors found that dopaminergic ACs and M1-type melanopsin intrinsically photosensitive retinal ganglion cells (ipRGCs), both of which exhibit neurite stratification predominantly within the S1 sublamina of the IPL in wild-type retinas, extend aberrant processes into S4/S5 in PlexA4-deficient retina (Matsuoka et al., 2011a; Figure 3A). Since PlexA4 is expressed by dopaminergic ACs but not by M1-type ipRGCs, this result suggests that the M1-type ipRGC dendritic stratification deficit within the IPL of PlexA4-deficient retina is likely a secondary consequence of defects in AC stratification within the IPL of the PlexA4-deficient retina, providing further support for ACs directing RGC dendritic stratification in the IPL (Stacy and Wong, 2003; Mumm et al., 2006; Matsuoka et al., 2011a). Sema6A and its receptor PlexA4 exhibit complementary protein expression patterns within the IPL, suggesting that Sema6A functions as a repulsive barrier within the IPL for neuronal processes expressing PlexA4 (Matsuoka et al., 2011a). Sema6A mutants show the same defects in neurite stratification within the IPL as observed in PlexA4 mutants (Matsuoka et al., 2011a; Figure 3A). Thus, these results show that Sema6A is a functional ligand for PlexA4, required for regulating select retinal neurite stratification in vivo (Matsuoka et al., 2011a; Figure 3A).

Bottom Line: The major semaphorin receptors are plexins and neuropilins, however other receptors and co-receptors also mediate signaling by semaphorins.Upon semaphorin binding to their receptors, downstream signaling molecules transduce this event within cells to mediate further events, including alteration of microtubule and actin cytoskeletal dynamics.Here, I review recent studies on semaphorin signaling in vertebrate neural circuit assembly, with the goal of highlighting how this diverse family of cues and receptors imparts exquisite specificity to neural complex connectivity.

View Article: PubMed Central - PubMed

Affiliation: Division of Developmental Biology, Cincinnati Children's Hospital Medical Center Cincinnati, OH, USA.

ABSTRACT
Neural circuit formation requires the coordination of many complex developmental processes. First, neurons project axons over long distances to find their final targets and then establish appropriate connectivity essential for the formation of neuronal circuitry. Growth cones, the leading edges of axons, navigate by interacting with a variety of attractive and repulsive axon guidance cues along their trajectories and at final target regions. In addition to guidance of axons, neuronal polarization, neuronal migration, and dendrite development must be precisely regulated during development to establish proper neural circuitry. Semaphorins consist of a large protein family, which includes secreted and cell surface proteins, and they play important roles in many steps of neural circuit formation. The major semaphorin receptors are plexins and neuropilins, however other receptors and co-receptors also mediate signaling by semaphorins. Upon semaphorin binding to their receptors, downstream signaling molecules transduce this event within cells to mediate further events, including alteration of microtubule and actin cytoskeletal dynamics. Here, I review recent studies on semaphorin signaling in vertebrate neural circuit assembly, with the goal of highlighting how this diverse family of cues and receptors imparts exquisite specificity to neural complex connectivity.

No MeSH data available.