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Journal of Psychiatry & Neuroscience :... 2024Critical adolescent neural refinement is controlled by the DCC (deleted in colorectal cancer) protein, a receptor for the netrin-1 guidance cue. We sought to describe...
Disproportionate neuroanatomical effects of haploinsufficiency in adolescence compared with adulthood: links to dopamine, connectivity, covariance, and gene expression brain maps in mice.
BACKGROUND
Critical adolescent neural refinement is controlled by the DCC (deleted in colorectal cancer) protein, a receptor for the netrin-1 guidance cue. We sought to describe the effects of reduced on neuroanatomy in the adolescent and adult mouse brain.
METHODS
We examined neuronal connectivity, structural covariance, and molecular processes in a -haploinsufficient mouse model, compared with wild-type mice, using new, custom analytical tools designed to leverage publicly available databases from the Allen Institute.
RESULTS
We included 11 -haploinsufficient mice and 16 wild-type littermates. Neuroanatomical effects of haploinsufficiency were more severe in adolescence than adulthood and were largely restricted to the mesocorticolimbic dopamine system. The latter finding was consistent whether we identified the regions of the mesocorticolimbic dopamine system a priori or used connectivity data from the Allen Brain Atlas to determine de novo where these dopamine axons terminated. Covariance analyses found that haploinsufficiency disrupted the coordinated development of the brain regions that make up the mesocorticolimbic dopamine system. Gene expression maps pointed to molecular processes involving the expression of , (encoding DCC's co-receptor), and (encoding its ligand, netrin-1) as underlying our structural findings.
LIMITATIONS
Our study involved a single sex (males) at only 2 ages.
CONCLUSION
The neuroanatomical phenotype of haploinsufficiency described in mice parallels that observed in -haploinsufficient humans. It is critical to understand the haploinsufficient mouse as a clinically relevant model system.
Topics: Animals; DCC Receptor; Haploinsufficiency; Brain; Dopamine; Mice; Male; Gene Expression; Neural Pathways; Age Factors; Female; Mice, Inbred C57BL; Aging
PubMed: 38692693
DOI: 10.1503/jpn.230106 -
Neoplasia (New York, N.Y.) 2000Chromosome 18q is frequently deleted in lung cancers, and a common region of 18q deletions was mapped to chromosome 18q21. Since the DCC candidate tumor suppressor gene...
Chromosome 18q is frequently deleted in lung cancers, and a common region of 18q deletions was mapped to chromosome 18q21. Since the DCC candidate tumor suppressor gene has been mapped in this region, mutation and expression of the DCC gene were examined in 46 lung cancer cell lines, consisting of 14 small cell lung carcinomas (SCLCs) and 32 non-small cell lung carcinomas (NSCLCs), to elucidate the pathogenetic significance of DCC alterations in human lung carcinogenesis. A heterozygous missense mutation was detected in a NSCLC cell line, Ma26, while homozygous deletion was not detected in any of the cell lines. The DCC gene was expressed in 11 (24%) of the 46 cell lines, and the incidence of DCC expression was significantly higher in SCLCs (7/14, 50%) than in NSCLCs (4/32, 13%) (P = .01, Fisher's exact test). Therefore, genetic alterations of DCC are infrequent; however, the levels of DCC expression vary among lung cancer cells, in particular, between SCLCs and NSCLCs. The present result does not implicate DCC as a specific mutational target of 18q deletions in human lung cancer; however, it suggests that DCC is a potential target of inactivation by genetic defects including intron or promoter mutations and/or epigenetic alterations. The present result also suggests that DCC expression is associated with some properties of SCLCs, such as a neuroendocrine (NE) feature.
Topics: Amino Acid Substitution; Carcinoma, Non-Small-Cell Lung; Carcinoma, Small Cell; Cell Adhesion Molecules; DCC Receptor; Genes, DCC; Humans; Lung Neoplasms; Mutation; Polymerase Chain Reaction; Polymorphism, Single-Stranded Conformational; Receptors, Cell Surface; Tumor Cells, Cultured; Tumor Suppressor Proteins
PubMed: 11005564
DOI: 10.1038/sj.neo.7900094 -
Cell Mar 1998
Review
Topics: Animals; Colonic Neoplasms; Disease Progression; Genes, APC; Genes, DCC; Genes, Tumor Suppressor; Humans; Mice; Signal Transduction; Transforming Growth Factor beta
PubMed: 9506511
DOI: 10.1016/s0092-8674(00)81124-1 -
The American Journal of Pathology Feb 2022Next-generation sequencing has enabled the collection of large biological data sets, allowing novel molecular-based classification methods to be developed for increased...
Next-generation sequencing has enabled the collection of large biological data sets, allowing novel molecular-based classification methods to be developed for increased understanding of disease. miRNAs are small regulatory RNA molecules that can be quantified using next-generation sequencing and are excellent classificatory markers. Herein, a deep cancer classifier (DCC) was adapted to differentiate neoplastic from nonneoplastic samples using comprehensive miRNA expression profiles from 1031 human breast and skin tissue samples. The classifier was fine-tuned and evaluated using 750 neoplastic and 281 nonneoplastic breast and skin tissue samples. Performance of the DCC was compared with two machine-learning classifiers: support vector machine and random forests. In addition, performance of feature extraction through the DCC was also compared with a developed feature selection algorithm, cancer specificity. The DCC had the highest performance of area under the receiver operating curve and high performance in both sensitivity and specificity, unlike machine-learning and feature selection models, which often performed well in one metric compared with the other. In particular, deep learning had noticeable advantages with highly heterogeneous data sets. In addition, our cancer specificity algorithm identified candidate biomarkers for differentiating neoplastic and nonneoplastic tissue samples (eg, miR-144 and miR-375 in breast cancer and miR-375 and miR-451 in skin cancer).
Topics: Breast Neoplasms; Female; Gene Expression Profiling; Humans; Machine Learning; MicroRNAs; RNA, Neoplasm
PubMed: 34774515
DOI: 10.1016/j.ajpath.2021.10.012 -
Development (Cambridge, England) Aug 2023The Netrin receptor Dcc and its Drosophila homolog Frazzled play crucial roles in diverse developmental process, including axon guidance. In Drosophila, Fra regulates...
The Netrin receptor Dcc and its Drosophila homolog Frazzled play crucial roles in diverse developmental process, including axon guidance. In Drosophila, Fra regulates midline axon guidance through a Netrin-dependent and a Netrin-independent pathway. However, what molecules regulate these distinct signaling pathways remain unclear. To identify Fra-interacting proteins, we performed affinity purification mass spectrometry to establish a neuronal-specific Fra interactome. In addition to known interactors of Fra and Dcc, including Netrin and Robo1, our screen identified 85 candidate proteins, the majority of which are conserved in humans. Many of these proteins are expressed in the ventral nerve cord, and gene ontology, pathway analysis and biochemical validation identified several previously unreported pathways, including the receptor tyrosine phosphatase Lar, subunits of the COP9 signalosome and Rho-5, a regulator of the metalloprotease Tace. Finally, genetic analysis demonstrates that these genes regulate axon guidance and may define as yet unknown signaling mechanisms for Fra and its vertebrate homolog Dcc. Thus, the Fra interactome represents a resource to guide future functional studies.
Topics: Animals; Humans; Receptors, Cell Surface; Drosophila Proteins; Netrin Receptors; Nerve Tissue Proteins; Axons; Axon Guidance; Receptors, Immunologic; Drosophila; Netrins; Netrin-1; Receptor-Like Protein Tyrosine Phosphatases
PubMed: 37526651
DOI: 10.1242/dev.201636 -
Molecular Brain Apr 2020The receptor deleted in colorectal cancer (DCC) and its ligand netrin-1 are essential for axon guidance during development and are expressed by neurons in the mature...
The receptor deleted in colorectal cancer (DCC) and its ligand netrin-1 are essential for axon guidance during development and are expressed by neurons in the mature brain. Netrin-1 recruits GluA1-containing α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) and is critical for long-term potentiation (LTP) at CA3-CA1 hippocampal Schaffer collateral synapses, while conditional DCC deletion from glutamatergic neurons impairs hippocampal-dependent spatial memory and severely disrupts LTP induction. DCC co-fractionates with the detergent-resistant component of postsynaptic density, yet is enriched in axonal growth cones that differentiate into presynaptic terminals during development. Specific presynaptic and postsynaptic contributions of DCC to the function of mature neural circuits have yet to be identified. Employing hippocampal subregion-specific conditional deletion of DCC, we show that DCC loss from CA1 hippocampal pyramidal neurons resulted in deficits in spatial memory, increased resting membrane potential, abnormal dendritic spine morphology, weaker spontaneous excitatory postsynaptic activity, and reduced levels of postsynaptic adaptor and signaling proteins; however, the capacity to induce LTP remained intact. In contrast, deletion of DCC from CA3 neurons did not induce detectable changes in the intrinsic electrophysiological properties of CA1 pyramidal neurons, but impaired performance on the novel object place recognition task as well as compromised excitatory synaptic transmission and LTP at Schaffer collateral synapses. Together, these findings reveal specific pre- and post-synaptic contributions of DCC to hippocampal synaptic plasticity underlying spatial memory.
Topics: Aging; Animals; CA1 Region, Hippocampal; CA3 Region, Hippocampal; DCC Receptor; Dendritic Spines; Gene Deletion; Glutamic Acid; Hippocampus; Memory Consolidation; Mice, Inbred C57BL; Neurons; Pyramidal Cells; Spatial Memory; Synapses
PubMed: 32264905
DOI: 10.1186/s13041-020-00597-2 -
Developmental Medicine and Child... Jun 2020Pathogenic variants in the gene encoding deleted in colorectal cancer (DCC) are the first genetic cause of isolated agenesis of the corpus callosum (ACC). Here we...
Pathogenic variants in the gene encoding deleted in colorectal cancer (DCC) are the first genetic cause of isolated agenesis of the corpus callosum (ACC). Here we present the detailed neurological, brain magnetic resonance imaging (MRI), and neuropsychological characteristics of 12 individuals from three families with pathogenic variants in DCC (aged 8-50y), who showed ACC and mirror movements (n=5), mirror movements only (n=2), ACC only (n=3), or neither ACC nor mirror movements (n=2). There was heterogeneity in the neurological and neuroimaging features on brain MRI, and performance across neuropsychological domains ranged from extremely low (impaired) to within normal limits (average). Our findings show that ACC and/or mirror movements are associated with low functioning in select neuropsychological domains and a DCC pathogenic variant alone is not sufficient to explain the disability. WHAT THIS PAPER ADDS: Neuropsychological impairment severity is related to presence of mirror movements and/or agenesis of the corpus callosum. A DCC pathogenic variant in isolation is associated with the best prognosis.
Topics: Adolescent; Adult; Agenesis of Corpus Callosum; Child; Cohort Studies; DCC Receptor; Female; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Movement Disorders; Mutation; Neuropsychological Tests; Prognosis; Young Adult
PubMed: 32060908
DOI: 10.1111/dmcn.14486 -
Whole-Exome Sequencing Identifies Pathogenic Germline Variants in Patients with Lynch-Like Syndrome.Cancers Aug 2022Lynch syndrome (LS) is the most common hereditary colorectal cancer (CRC) syndrome, characterized by germline pathogenic variants in mismatch repair (MMR)-related genes...
Lynch syndrome (LS) is the most common hereditary colorectal cancer (CRC) syndrome, characterized by germline pathogenic variants in mismatch repair (MMR)-related genes that lead to microsatellite instability. Patients who meet the clinical criteria for LS and MMR deficiency and without any identified germline pathogenic variants are frequently considered to have Lynch-like syndrome (LLS). These patients have a higher risk of CRC and extracolonic tumors, and little is known about their underlying genetic causes. We investigated the germline spectrum of LLS patients through whole-exome sequencing (WES). A total of 20 unrelated patients with MMR deficiency who met the clinical criteria for LS and had no germline variant were subjected to germline WES. Variant classification was performed according to the American College of Medical Genetics and Genomics (ACMG) criteria. Pathogenic/likely pathogenic variants were identified in 35% of patients in known cancer genes such as and . Besides this, rare and potentially pathogenic variants were identified in the DNA repair gene and other cancer-related genes such as , , and . Our study demonstrates the germline mutational status of LLS patients, a population at high risk of colorectal cancer.
PubMed: 36077770
DOI: 10.3390/cancers14174233 -
Scientific Reports Feb 2017Understanding the loss of conserved genes is critical for determining how phenotypic diversity is generated. Here we focus on the evolution of DCC, a gene that encodes a...
Understanding the loss of conserved genes is critical for determining how phenotypic diversity is generated. Here we focus on the evolution of DCC, a gene that encodes a highly conserved neural guidance receptor. Disruption of DCC in animal models and humans results in major neurodevelopmental defects including commissural axon defects. Here we examine DCC evolution in birds, which is of particular interest as a major model system in neurodevelopmental research. We found the DCC containing locus was disrupted several times during evolution, resulting in both gene losses and faster evolution rate of salvaged genes. These data suggest that DCC had been lost independently twice during bird evolution, including in chicken and zebra finch, whereas it was preserved in many other closely related bird species, including ducks. Strikingly, we observed that commissural axon trajectory appeared similar regardless of whether DCC could be detected or not. We conclude that the DCC locus is susceptible to genomic instability leading to independent disruptions in different branches of birds and a significant influence on evolution rate. Overall, the phenomenon of loss or molecular evolution of a highly conserved gene without apparent phenotype change is of conceptual importance for understanding molecular evolution of key biological processes.
Topics: Animals; Birds; Evolution, Molecular; Genes, DCC; Genetic Loci; Genomic Instability
PubMed: 28240293
DOI: 10.1038/srep42029 -
International Journal of Cancer Apr 2017We conducted a prospective study to assess the prognostic impact of selected copy number variations (CNVs) in Stage II-III microsatellite stable (MSS) colon cancer. A...
We conducted a prospective study to assess the prognostic impact of selected copy number variations (CNVs) in Stage II-III microsatellite stable (MSS) colon cancer. A total of 401 patients were included from 01/2004 to 01/2009. The CNVs in 8 selected target genes, DCC/18q, EGFR/7p, TP53/17p, BLK/8p, MYC/8q, APC/5q, ERBB2/17q and STK6/20q, were detected using a quantitative multiplex polymerase chain reaction of short fluorescent fragment (QMPSF) method. The primary end-point was the impact of the CNVs on the 4-year disease-free survival (DFS). The recurrence rate at 4 years was 20.9%, corresponding to 14% Stage II patients versus 31% Stage III patients (p < 0.0001). The 4-year DFS was significantly decreased in patients with a loss at DCC/18q (p = 0.012) and a gain at ERBB2/17q (p = 0.041). The multivariate analysis demonstrated that Stage III, a loss at DCC/18q and a gain at ERBB2/17q were independent factors associated with DFS. A combination of DCC/18q and ERBB2/17q was also associated with relapse, with the hazard ratio increasing from 1 to 2.4 (95% confidence interval (CI), 1.5-4.1) and 3.1 (95% CI, 1.2-8.4) in the presence of 0, 1 or 2 alterations, respectively (p = 0.0013). CNVs in DCC/18q and ERBB2/17q are significantly associated with DFS in Stage II-III MSS colon cancer.
Topics: Aged; Carcinoma; Colonic Neoplasms; DCC Receptor; DNA Copy Number Variations; DNA Mutational Analysis; Disease-Free Survival; Female; Humans; Loss of Heterozygosity; Male; Microsatellite Repeats; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local; Phenotype; Polymerase Chain Reaction; Prognosis; Proportional Hazards Models; Prospective Studies; Proto-Oncogene Proteins B-raf; Receptor, ErbB-2; Receptors, Cell Surface; Treatment Outcome; Tumor Suppressor Proteins
PubMed: 28006840
DOI: 10.1002/ijc.30584