F-spondin: A gene expressed at high levels in the floor plate encodes a secreted protein that promotes neural cell adhesion and neurite extension

Klar, Avihu; Baldassare, Mark; Jessell, Thomas M.

doi:10.1016/0092-8674(92)90121-r

Cited by 367 publications

(267 citation statements)

References 70 publications

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“…SPON1, a member of the spondin family of genes, is highly expressed in the embryonic neural floor plate, and it is essential for neural growth and cell adhesion (16,17). Prior studies implicate this same gene in brain structural development and neural connectivity, and its expression declines with aging (18).…”

Section: Resultsmentioning

confidence: 99%

Genome-wide scan of healthy human connectome discoversSPON1gene variant influencing dementia severity

Jahanshad

Rajagopalan

Hou

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

147

128

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Aberrant connectivity is implicated in many neurological and psychiatric disorders, including Alzheimer's disease and schizophrenia. However, other than a few disease-associated candidate genes, we know little about the degree to which genetics play a role in the brain networks; we know even less about specific genes that influence brain connections. Twin and family-based studies can generate estimates of overall genetic influences on a trait, but genome-wide association scans (GWASs) can screen the genome for specific variants influencing the brain or risk for disease. To identify the heritability of various brain connections, we scanned healthy young adult twins with high-field, highangular resolution diffusion MRI. We adapted GWASs to screen the brain's connectivity pattern, allowing us to discover genetic variants that affect the human brain's wiring. The association of connectivity with the SPON1 variant at rs2618516 on chromosome 11 (11p15.2) reached connectome-wide, genome-wide significance after stringent statistical corrections were enforced, and it was replicated in an independent subsample. rs2618516 was shown to affect brain structure in an elderly population with varying degrees of dementia. Older people who carried the connectivity variant had significantly milder clinical dementia scores and lower risk of Alzheimer's disease. As a posthoc analysis, we conducted GWASs on several organizational and topological network measures derived from the matrices to discover variants in and around genes associated with autism (MACROD2), development (NEDD4), and mental retardation (UBE2A) significantly associated with connectivity. Connectome-wide, genome-wide screening offers substantial promise to discover genes affecting brain connectivity and risk for brain diseases.diffusion tensor imaging | neuroimaging genetics | graph theory | HARDI tractography | multiple comparisons correction H uman brain anatomy involves a complex network of structural and functional pathways that connect anatomically distinct regions. These pathways can be visualized, on a gross anatomical scale, with diffusion imaging-based tractography (1). Neural pathways change as our brains develop (2, 3) and are altered in neurodegenerative conditions, including Alzheimer's disease (4). Our individual genetic makeup exerts a strong influence on the functional synchronization of brain regions (5) and the patterning of cortical structure (6, 7), but particular genes that impact the brain's neural connectivity are still largely unknown.To empower the search for genes that affect the brain's connectivity patterns, we first studied a large twin and family cohort consisting of 366 young adults (ages 20-29 y) from 223 families. We used anatomical brain MRI combined with high-angular resolution diffusion imaging (HARDI) at high magnetic field (4 T) to subdivide cortical regions into areas of known structure and function (8), while also mapping the white matter fiber pathways between them with high-resolution tractography. We defined connectivity maps...

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Section: Resultsmentioning

confidence: 99%

Genome-wide scan of healthy human connectome discoversSPON1gene variant influencing dementia severity

Jahanshad

Rajagopalan

Hou

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

147

128

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“…The results of recent studies aimed at perturbing the function of other floor plate-associated proteins further support a role for contact-dependent attractants/repellents in the regulation of midline crossing. F-spondin, an extracellular matrix protein that was originally identified in a subtractive hybridization screen for cDNAs encoding proteins enriched in the embryonic rat floor plate, is produced and secreted by floor plate cells (Klar et al, 1992). More recently, a chick homolog of F-spondin has been identified and soluble fusion proteins representing the thrombospondin type I repeat (TSR)-containing domain of this protein have been shown to bind to, and promote the outgrowth of, commissural growth axons in vitro (Burstyn-Cohen et al, 1999).…”

Section: Vertebrate Spinal Cordmentioning

confidence: 99%

Axon guidance at the midline choice point

Kaprielian

Runko

Imondi

2001

Developmental Dynamics

146

108

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The central nervous system (CNS) of higher organisms is bilaterally-symmetric. The transfer of information between the two sides of the nervous system occurs through commissures formed by neurons that project axons across the midline to the contralateral side of the CNS. Interestingly, these axons cross the midline only once. Other neurons extend axons that never cross the midline; they project exclusively on their own (ipsilateral) side of the CNS. Thus, the midline is an important choice point for several classes of pathfinding axons. Recent studies demonstrate that specialized midline cells play critical roles in regulating the guidance of both crossing and non-crossing axons at the ventral midline of the developing vertebrate spinal cord and the Drosophila ventral nerve cord. For example, these cells secrete attractive cues that guide commissural axons over long distances to the midline of the CNS. Furthermore, shortrange interactions between guidance cues present on the surfaces of midline cells, and their receptors expressed on the surfaces of pathfinding axons, allow commissural axons to cross the midline only once and prevent ipsilaterally-projecting axons from entering the midline. Remarkably, the molecular composition of commissural axon surfaces is dynamically-altered as they cross the midline. Consequently, commissural axons become responsive to repulsive midline guidance cues that they had previously ignored on the ipsilateral side of the midline. Concomitantly, commissural axons lose responsiveness to attractive guidance cues that had initially attracted them to the midline. Thus, these exquisitely regulated guidance systems prevent commissural axons from lingering within the confines of the midline and allow them to pioneer an appropriate pathway on the contralateral side of the CNS. Many aspects of midline guidance are controlled by mechanistically and evolutionarily-conserved ligand-receptor systems. Strikingly, recent studies demonstrate that these receptors are modular; the ectodomains determine ligand recognition and the cytoplasmic domains specify the response of an axon to a given guidance cue. Despite rapid and dramatic progress in elucidating the molecular mechanisms that control midline guidance, many questions remain.

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“…In birds, F-spondin protein is deposited in the caudal somite and the ventral medial scelrotome (14). In both rodents and birds, F-spondin is expressed in the floor plate (9,13). Immunohistochemical studies demonstrate that there is a difference in the proteins deposition along the caudal-rostral axis of the central nervous system.…”

Section: F-spondin Ismentioning

confidence: 99%

“…F-spondin, a secreted adhesion molecule expressed in the embryonic floor plate of vertebrates (9)(10)(11)(12)(13), and the caudal somite of birds (14), plays a similar dual role in patterning the nervous system. F-spondin promotes adhesion and outgrowth of commissural axons and inhibits adhesion of neural crest cells.…”

mentioning

confidence: 99%

F-spondin is a contact-repellent molecule for embryonic motor neurons

Tzarfati-Majar

Burstyn‐Cohen

Klar

2001

Proc. Natl. Acad. Sci. U.S.A.

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The floor plate plays a key role in patterning axonal trajectory in the embryonic spinal cord by providing both long-range and local guidance cues that promote or inhibit axonal growth toward and across the ventral midline of the spinal cord, thus acting as an intermediate target for a number of crossing (commissural) and noncrossing (motor) axons. F-spondin, a secreted adhesion molecule expressed in the embryonic floor plate and the caudal somite of birds, plays a dual role in patterning the nervous system. It promotes adhesion and outgrowth of commissural axons and inhibits adhesion of neural crest cells. In the current study, we demonstrate that outgrowth of embryonic motor axons also is inhibited by F-spondin protein in a contact-repulsion fashion. Three independent lines of evidence support our hypothesis: substrateattached F-spondin inhibits outgrowth of dissociated motor neurons in an outgrowth assay; F-spondin elicits acute growth cone collapse when applied to cultured motor neurons; and challenging ventral spinal cord explants with aggregates of HEK 293 cells expressing F-spondin, causes contact-repulsion of motor neurites.Structural-functional studies demonstrate that the processed carboxyl-half protein that contains the thrombospondin type 1 repeats is more prominent in inhibiting outgrowth, suggesting that the processing of F-spondin is important for enhancing its inhibitory activity.

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F-spondin: A gene expressed at high levels in the floor plate encodes a secreted protein that promotes neural cell adhesion and neurite extension

Cited by 367 publications

References 70 publications

Genome-wide scan of healthy human connectome discoversSPON1gene variant influencing dementia severity

Genome-wide scan of healthy human connectome discoversSPON1gene variant influencing dementia severity

Axon guidance at the midline choice point

F-spondin is a contact-repellent molecule for embryonic motor neurons

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