Discoidin domain receptor 1 functions in axon extension of cerebellar granule neurons

Bhatt, Rupal S.; Tomoda, Toshifumi; Yin, Fei; Hatten, Mary E.

doi:10.1101/gad.821600

Cited by 81 publications

(61 citation statements)

References 39 publications

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“…21,22 In CNS, collagen-DDR1 signalling has been shown to be essential for granule neuron-axon formation. 23 In addition, we reported the expression of DDR1 in oligodendrocytes during mouse brain development and in a human oligodendroglial cell line; these data provide evidence for the potential involvement of DDR1 in the myelination process. 24 Classically, schizophrenia investigation has tended to focus on neuron function, but, increasingly, data have been produced to support the hypothesis that white matter oligodendrocytes are also important in the development of the disease.…”

Section: Introductionmentioning

confidence: 54%

The discoidin domain receptor 1 as a novel susceptibility gene for schizophrenia

et al. 2007

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Evidence suggests that myelin alterations could predispose to schizophrenia. Reduced expression of several myelin genes has been observed in schizophrenia patients. Recently, we identified the discoidin domain receptor 1 (DDR1; located at human chromosome 6p21.3) as a myelin gene in the mouse model and in a human oligodendroglial cell line. In the present study we screened for single nucleotide polymorphisms (SNPs) in the DNA from 100 schizophrenia patients. We identified a novel mutation within exon 10 that produces the amino-acid substitution N502S in the a-d isoforms, and M475V in the e isoform. However the frequency of the mutation (2%) was similar in schizophrenia patients and in control subjects. In a casecontrol assessment with 389 schizophrenic patients and 615 controls, we identified one SNP (SNP9, rs1049623) associated with schizophrenia (odds ratio = 1.44, 95% confidence interval: 1.15-1.79, adjusted P = 0.0016). This association was confirmed in haplotype analysis; the SNPs 9-10-11 (rs1049623, rs2267641 and rs2239518) haplotype remaining significant even after adjustment for multiple testing (adjusted P = 0.0136). Of note was a strong gender dependence in the association, that is, statistical significance restricted to men (adjusted P-value = 0.0002). Regression analysis of DDR1 mRNA expression in peripheral blood lymphocytes from schizophrenia patients showed that the presence of the G allele significantly decreased the relative number of mRNA copies in a dose-dependent manner (P = 0.003). These data suggest that the risk haplotype tags a cis-acting variant involved in the transcription regulation system of the gene. In conclusion, we propose the DDR1 as a new susceptibility gene for schizophrenia.

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Section: Introductionmentioning

confidence: 54%

The discoidin domain receptor 1 as a novel susceptibility gene for schizophrenia

et al. 2007

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“…DDR1 is important for axon growth of cerebellar granule neurons [Bhatt et al, 2000], and for normal development of the mammary gland . DDR1 expression and activation are triggered by apoptotic stimuli, and promote cell survival by a mechanism dependent on activation of MAPK and induction of p53 [Ongusaha et al, 2003].…”

Section: Introductionmentioning

confidence: 99%

Collagen type I selectively activates ectodomain shedding of the discoidin domain receptor 1: Involvement of Src tyrosine kinase

Slack

Siniaia

Blusztajn

2006

J of Cellular Biochemistry

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The discoidin domain receptor 1 (DDR1) is a receptor tyrosine kinase that is highly expressed in breast carcinoma cells. Upon binding to collagen, DDR1 undergoes autophosphorylation followed by limited proteolysis to generate a tyrosine phosphorylated C-terminal fragment (CTF). Although it was postulated that this fragment is formed as a result of shedding of the N-terminal ectodomain, collagen-dependent release of the DDR1 extracellular domain has not been demonstrated. We now report that, in conjunction with CTF formation, collagen type I stimulates concentration-dependent, saturable shedding of the DDR1 ectodomain from two carcinoma cell lines, and from transfected cells. In contrast, collagen did not promote cleavage of other transmembrane proteins including the amyloid precursor protein (APP), ErbB2, and E-cadherin. Collagen-dependent tyrosine phosphorylation and proteolysis of DDR1 in carcinoma cells were reduced by a pharmacologic Src inhibitor. Moreover, expression of a dominant negative Src mutant protein in human embryonic kidney cells inhibited collagen-dependent phosphorylation and shedding of co-transfected DDR1. The hydroxamate-based metalloproteinase inhibitor TAPI-1 (tumor necrosis factor-α protease inhibitor-1), and tissue inhibitor of metalloproteinase (TIMP)-3, also blocked collagen-evoked DDR1 shedding, but did not reduce levels of the phosphorylated CTF. Neither shedding nor CTF formation were affected by the γ-secretase inhibitor, L-685,458. The results demonstrate that collagen-evoked ectodomain cleavage of DDR1 is mediated in part by Src-dependent activation or recruitment of a matrix-or disintegrin metalloproteinase, and that CTF formation can occur independently of ectodomain shedding. Delayed shedding of the DDR1 ectodomain may represent a mechanism that limits DDR1-dependent cell adhesion and migration on collagen matrices. Keywords zinc-dependent metalloproteinase; amyloid precursor protein; tyrosine phosphorylation; TIMP (tissue inhibitor of metalloproteinase)

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“…Although EGL differentiation has been well characterized, much less is known about the genes that govern this process (Goldowitz and Hamre, 1998;Dahmane and Ruiz-i-Altaba, 1999;Bhatt et al, 2000). To search for the genes involved in this process, microarray assays were performed using cerebellar cells prepared at P4, P6, P8, and P10.…”

Section: Introductionmentioning

confidence: 99%

Signaling by Bone Morphogenetic Proteins and Smad1 Modulates the Postnatal Differentiation of Cerebellar Cells

Angley¹,

Kumar²,

Dinsio

et al. 2003

J. Neurosci.

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Previous studies have demonstrated that bone morphogenetic proteins (BMPs) activate the Smad1 signaling pathway to regulate cell determination and differentiation in the embryonic nervous system. Studies examining gene and protein expression in the rat cerebellum suggest that this pathway also regulates postnatal differentiation. Using microarrays, we found that Smad1 mRNA expression in the cerebellum increases transiently at postnatal day 6 (P6). Immunohistochemistry and Western blots showed that Smad1 and BMP4 proteins are present in the cerebellum, and that their expression also changes postnatally. The proteins are detectable at P4 -P6, a stage at which most cerebellar cells reside in the external germinal layer (EGL), where they extensively differentiate. The levels become maximal at P8 -P10, when neurons begin to migrate from the EGL into their mature positions in the internal granule layer. In cerebellar cultures prepared at P6 or P10, BMP4 activates Smad1 signaling to modulate cell differentiation. Brief BMP4 application caused Smad1 translocation from the neuronal cytoplasm into the nucleus, where it is known to regulate transcription in association with Smad4. Longer BMP4 treatment promoted the differentiation of both neuronal and non-neuronal cells. By 3 d, neuronal processes appeared more fasciculated, and the level of synaptotagmin, a protein found in synaptic vesicles, increased. In addition, many astroglial cells became more branched and stellate in morphology. The BMP-induced changes were reduced by treatment with antisense oligonucleotides to Smad1 or Smad4. These findings in vivo and in culture suggest that BMP4 and Smad1 signaling participate in regulating postnatal cerebellar differentiation.

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Discoidin domain receptor 1 functions in axon extension of cerebellar granule neurons

Cited by 81 publications

References 39 publications

The discoidin domain receptor 1 as a novel susceptibility gene for schizophrenia

The discoidin domain receptor 1 as a novel susceptibility gene for schizophrenia

Collagen type I selectively activates ectodomain shedding of the discoidin domain receptor 1: Involvement of Src tyrosine kinase

Signaling by Bone Morphogenetic Proteins and Smad1 Modulates the Postnatal Differentiation of Cerebellar Cells

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