A point mutation in Semaphorin 4A associates with defective endosomal sorting and causes retinal degeneration

Nojima, Satoshi; Toyofuku, Toshihiko; Kamao, Hiroyuki; Ishigami, Chie; Kaneko, Jun; Okuno, Tatsusada; Takamatsu, Hyota; Ito, Daisuke; Kang, Sujin; Kimura, Tetsuya; Yoshida, Yūji; Morimoto, Keiko; Maeda, Yohei; Ogata, Atsushi; Ikawa, Masahito; Morii, Eiichi; Aozasa, Katsuyuki; Takagi, Junichi; Takahashi, Masayo; Kumanogoh, Atsushi

doi:10.1038/ncomms2420

Cited by 23 publications

(19 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Sema4A is expressed in retinal ganglion cells, inner retinal neurons and RPE cells during the time at which photoreceptors establish intimate contacts with the RPE. In RPE cells, Sema4A is localized to the apical membrane . These observations suggest that Sema4A may play a role in interactions between RPE cells and photoreceptors.…”

Section: Introductionmentioning

confidence: 74%

See 1 more Smart Citation

Up‐regulation of semaphorin 4A expression in human retinal pigment epithelial cells by PACAP released from cocultured neural cells

Hirata

Yamane

et al. 2014

Cell Biochemistry & Function

View full text Add to dashboard Cite

Development and homeostasis of multicellular organisms require interactions between neighbouring cells. We recently established an in vitro model of cell-cell interaction based on a collagen vitrigel membrane. We have now examined the role of neural cells in retinal homeostasis by coculture of human retinal pigment epithelial (RPE) cells and neural cells on opposite sides of such a membrane. The neural cells (differentiated PC12 cells) induced up-regulation of semaphorin 4A (Sema4A), a member of the semaphorin family of neural guidance proteins, in RPE (ARPE19) cells. This effect of the neural cells was mimicked by the neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) and was abolished by the PACAP antagonist PACAP(6-38). Coculture with neural cells or stimulation with PACAP also induced the phosphorylation of extracellular-signal-regulated kinase in ARPE19 cells, and this effect of the neural cells was inhibited by PACAP(6-38). Finally, among various cytokines examined, only the amount of interleukin-6 released by cocultures of ARPE19 and neural cells differed from that released by ARPE19 cells cultured alone. Interleukin-6 was not detected in culture supernatants of neural cells, and the reduction in the amount of interleukin-6 released by the cocultures compared with that released by ARPE19 cells alone was prevented by PACAP(6-38). Our findings suggest that PACAP released from retinal neural cells (photoreceptors or optic nerve cells) may regulate Sema4A expression in RPE cells and thereby contribute to the maintenance of retinal structure and function. Development and homeostasis of multicellular organisms require interactions between neighbouring cells. With the use of a coculture system based on a collagen vitrigel membrane, we have now shown that neural cells induce up-regulation of the neural guidance protein Sema4A in RPE cells. This effect of neural cells appears to be mediated by the neuropeptide PACAP. PACAP released from retinal neural cells (photoreceptors or optic nerve cells) may thus regulate Sema4A expression in RPE cells and thereby contribute to the maintenance of retinal structure and function.

show abstract

Section: Introductionmentioning

confidence: 74%

“…In RPE cells, Sema4A is localized to the apical membrane. 14 These observations suggest that Sema4A may play a role in interactions between RPE cells and photoreceptors.…”

Section: Introductionmentioning

confidence: 90%

Up‐regulation of semaphorin 4A expression in human retinal pigment epithelial cells by PACAP released from cocultured neural cells

Hirata

Yamane

et al. 2014

Cell Biochemistry & Function

View full text Add to dashboard Cite

show abstract

“…An analysis of a series of knock-in mouse lines carrying mutated alleles of Sema4A demonstrated that expression of Sema4A(F350C) caused severe retinal degeneration (Nojima et al 2013). In the RPE, Sema4A(F350C) tends to aggregate, and the resultant mislocalization of Sema4A protein may lead to the impaired endosomal sorting of molecules such as prosaposin and retinoid-binding proteins.…”

Section: Sema4a In Retinal Degenerationmentioning

confidence: 98%

Semaphorin in the Retinal System

Toyofuku

2015

Semaphorins

Self Cite

View full text Add to dashboard Cite

The vertebrate retina is a light-sensitive layer of tissue that lines the inner surface of the eye. Light striking the retina initiates a cascade of chemical and electrical events that ultimately trigger nerve impulses, which are sent to various visual centers of the brain through the fibers of the optic nerve. Each axis of the retina is mapped independently using different mechanisms and sets of axonguidance molecules, such as the semaphorins, which are expressed in gradients to achieve projections from points in the retina to points in the target regions of the brain. In animal models, mutations in several of the guidance molecules disrupt axonal projections at specific sites, whereas mutation of one of the semaphorins reduces photoreceptor survival. Understanding the molecular mechanisms of neural defects in a variety of animal models can provide valuable insights into the effects of each molecule in clinical disorders and may form the basis of future therapies to prevent retinal diseases. Keywords

show abstract

“…In fact, 3 mutations in the Sema4A gene have been identified in patients with retinal degenerative diseases: D345H, F350C, and R713Q 50 . Expression of Sema4A (F350C) causes severe retinal degeneration in a series of knock-in mouse lines carrying mutated alleles of Sema4A 51 . In addition, Sema4A (F350C) tends to aggregate in the RPE, and this abnormal localization may lead to impaired endosomal sorting of molecules including prosaposin.…”

Section: Sema4a and Retinal Degenerationmentioning

confidence: 99%

The role of Sema4A in angiogenesis, immune responses, carcinogenesis, and retinal systems

Ito¹,

Kumanogoh²

2016

Cell Adhesion & Migration

Self Cite

View full text Add to dashboard Cite

Semaphorins were originally identified as axon guidance cues that regulate the functional activity of axons in the nervous system. In addition, accumulating evidence indicates that semaphorins have multiple functions in physiological and pathogenic processes, including vascular development, tumor progression, and immune responses. Sema4A is a semaphorin expressed in immune cells, and is thus termed an “immune semaphorin.” Sema4A has 4 types of receptors: Plexin D family, Plexin B family, Tim-2, and Nrp-1. Recent studies suggest that Sema4A plays critical roles in many processes including cell–cell interactions, immune-cell activation, differentiation, and migration. In other studies, Sema4A is also associated with carcinogenesis and retinal systems. In this review, we summarize current knowledge regarding the biology of Sema4A in relation to angiogenesis, immune responses, colorectal cancer, and the retina.

show abstract

A point mutation in Semaphorin 4A associates with defective endosomal sorting and causes retinal degeneration

Cited by 23 publications

References 34 publications

Up‐regulation of semaphorin 4A expression in human retinal pigment epithelial cells by PACAP released from cocultured neural cells

Up‐regulation of semaphorin 4A expression in human retinal pigment epithelial cells by PACAP released from cocultured neural cells

Semaphorin in the Retinal System

The role of Sema4A in angiogenesis, immune responses, carcinogenesis, and retinal systems

Contact Info

Product

Resources

About