Agrin accumulates in the brain microvascular basal lamina during development of the blood‐brain barrier

Barber, Alistair J.; Lieth, Erich

doi:10.1002/(sici)1097-0177(199701)208:1<62::aid-aja6>3.0.co;2-#

Cited by 113 publications

(58 citation statements)

References 55 publications

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“…A novel function for agrin is a proposed role in maintaining cerebral microvascular impermeability insofar as agrin accumulates in the brain microvascular basement membranes during development of the blood-brain barrier (120). In both avian and murine brain, agrin accumulates on vessels around the time the vasculature becomes impermeable.…”

Section: Expression and Functional Propertiesmentioning

confidence: 99%

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MATRIX PROTEOGLYCANS: From Molecular Design to Cellular Function

Iozzo

1998

Annu. Rev. Biochem.

1,483

1,111

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The proteoglycan superfamily now contains more than 30 full-time molecules that fulfill a variety of biological functions. Proteoglycans act as tissue organizers, influence cell growth and the maturation of specialized tissues, play a role as biological filters and modulate growth-factor activities, regulate collagen fibrillogenesis and skin tensile strength, affect tumor cell growth and invasion, and influence corneal transparency and neurite outgrowth. Additional roles, derived from studies of mutant animals, indicate that certain proteoglycans are essential to life whereas others might be redundant.The review focuses on the most recent genetic and molecular biological studies of the matrix proteoglycans, broadly defined as proteoglycans secreted into the pericellular matrix. Special emphasis is placed on the molecular organization of the protein core, the utilization of protein modules, the gene structure and transcriptional control, and the functional roles of the various proteoglycans. When possible, proteoglycans have been grouped into distinct gene families and subfamilies offering a simplified nomenclature based on their protein core design. The structure-function relationship of some paradigmatic proteoglycans is discussed in depth and novel aspects of their biology are examined. CONTENTS

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Section: Expression and Functional Propertiesmentioning

confidence: 99%

“…In both avian and murine brain, agrin accumulates on vessels around the time the vasculature becomes impermeable. Moreover, the agrin isoform that accumulates at such loci lacks the 8-and 11-amino-acid sequences known to confer on agrin high potency in acetylcholine receptor clustering (120).…”

Section: Expression and Functional Propertiesmentioning

confidence: 99%

MATRIX PROTEOGLYCANS: From Molecular Design to Cellular Function

Iozzo

1998

Annu. Rev. Biochem.

1,483

1,111

View full text Add to dashboard Cite

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“…Agrin staining in the brain is most prominent in the blood vessels and in pial basement membranes (Barber and Lieth, 1997;Halfter et al, 1997). Moreover, neurons in the CNS have been shown to express mRNA encoding agrin isoforms that contain amino acid inserts at the B/z site (O'Connor et al, 1994;Stone and Nikolics, 1995).…”

Section: Agrin Localizes To Excitatory But Not Inhibitory Synapses Inmentioning

confidence: 99%

Synapse Loss in Cortex of Agrin-Deficient Mice after Genetic Rescue of Perinatal Death

Ksiazek¹,

Burkhardt²,

Lin³

et al. 2007

J. Neurosci.

109

111

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Agrin-deficient mice die at birth because of aberrant development of the neuromuscular junctions. Here, we examined the role of agrin at brain synapses. We show that agrin is associated with excitatory but not inhibitory synapses in the cerebral cortex. Most importantly, we examined the brains of agrin-deficient mice whose perinatal death was prevented by the selective expression of agrin in motor neurons. We find that the number of presynaptic and postsynaptic specializations is strongly reduced in the cortex of 5-to 7-week-old mice. Consistent with a reduction in the number of synapses, the frequency of miniature postsynaptic currents was greatly decreased. In accordance with the synaptic localization of agrin to excitatory synapses, changes in the frequency were only detected for excitatory but not inhibitory synapses. Moreover, we find that the muscle-specific receptor tyrosine kinase MuSK, which is known to be an essential component of agrin-induced signaling at the neuromuscular junction, is also localized to a subset of excitatory synapses. Finally, some components of the mitogen-activated protein (MAP) kinase pathway, which has been shown to be activated by agrin in cultured neurons, are deregulated in agrin-deficient mice. In summary, our results provide strong evidence that agrin plays an important role in the formation and/or the maintenance of excitatory synapses in the brain, and we provide evidence that this function involves MAP kinase signaling.

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“…More recently, agrin has been shown to be widely expressed in the rodent and avian central nervous system (1,6,7), with its highest expression observed during peak periods of synaptogenesis (8). It is localized within neurons (9) as well as in the basal lamina of the microvasculature (10) and in the developing optic tract (7,11). Agrin levels are transiently increased after seizure activity (12), and exogenous agrin induces cAMP response elementbinding protein phosphorylation in cultured neurons (9).…”

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confidence: 99%

Agrin in Alzheimer’s disease: Altered solubility and abnormal distribution within microvasculature and brain parenchyma

Donahue

Berzin

Rafii

et al. 1999

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

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Agrin is a heparan sulfate proteoglycan that is widely expressed in neurons and microvascular basal lamina in the rodent and avian central nervous system. Agrin induces the differentiation of nerve-muscle synapses, but its function in either normal or diseased brains is not known. Alzheimer's disease (AD) is characterized by loss of synapses, changes in microvascular architecture, and formation of neurofibrillary tangles and senile plaques. Here we have asked whether AD causes changes in the distribution and biochemical properties of agrin. Immunostaining of normal, aged human central nervous system revealed that agrin is expressed in neurons in multiple brain areas. Robust agrin immunoreactivity was observed uniformly in the microvascular basal lamina. In AD brains, agrin is highly concentrated in both diffuse and neuritic plaques as well as neurofibrillary tangles; neuronal expression of agrin also was observed. Furthermore, patients with AD had microvascular alterations characterized by thinning and fragmentation of the basal lamina. Detergent extraction and Western blotting showed that virtually all the agrin in normal brain is soluble in 1% SDS. In contrast, a large fraction of the agrin in AD brains is insoluble under these conditions, suggesting that it is tightly associated with ␤-amyloid. Together, these data indicate that the agrin abnormalities observed in AD are closely linked to ␤-amyloid deposition. These observations suggest that altered agrin expression in the microvasculature and the brain parenchyma contribute to the pathogenesis of AD.

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Agrin accumulates in the brain microvascular basal lamina during development of the blood‐brain barrier

Cited by 113 publications

References 55 publications

MATRIX PROTEOGLYCANS: From Molecular Design to Cellular Function

MATRIX PROTEOGLYCANS: From Molecular Design to Cellular Function

Synapse Loss in Cortex of Agrin-Deficient Mice after Genetic Rescue of Perinatal Death

Agrin in Alzheimer’s disease: Altered solubility and abnormal distribution within microvasculature and brain parenchyma

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