A balance between inductive and repressive signals determines optimal flowering time for successf... more A balance between inductive and repressive signals determines optimal flowering time for successful reproduction in seasonal environments (28, 29). Our data demonstrate the importance of the repressors SVP, FLM-b, and FLC, which affect flowering at different but partially overlapping temperature ranges (fig. S19). However, we cannot exclude the possibility that the importance of SVP and FLM-b may not extend to Arabidopsis winter annual accessions. At lower temperatures, increased SVP protein interacts with FLM-b to repress flowering by direct binding to downstream targets. At higher temperatures, SVP protein levels decline, allowing expression of the downstream target genes and enabling flowering at that temperature. We propose that repressive activity of SVP requires FLM-b in the same complex and that SVP protein stability modulates the abundance of the SVP-FLM-b repressor complex to regulate ambient temperature-responsive flowering. SVP-like proteins have conserved functions across plant species (30, 31); therefore, control of SVP-FLM-b repressor complex abundance could be a general strategy for plants to adjust the balance of inductive and repressive signals under fluctuating temperature conditions.
Author contributions: M.J.M., Y.H.H., and C.J.S. designed research; M.J.M., Y.H.H., and A.D. perf... more Author contributions: M.J.M., Y.H.H., and C.J.S. designed research; M.J.M., Y.H.H., and A.D. performed research; M.J.M. contributed new reagents/analytic tools; M.J.M., Y.H.H., and C.J.S. analyzed data; and M.J.M., Y.H.H., and C.J.S. wrote the paper. The authors declare no conflict of interest. 1 M.J.M. and Y.H.H. contributed equally to this work.
Background: Existing quantitative models of mouse cerebral cortical development are not fully con... more Background: Existing quantitative models of mouse cerebral cortical development are not fully constrained by experimental data.
Major histocompatibility complex class I (MHCI) genes were discovered unexpectedly in healthy CNS... more Major histocompatibility complex class I (MHCI) genes were discovered unexpectedly in healthy CNS neurons in a screen for genes regulated by neural activity. In mice lacking just 2 of the 50+ MHCI genes H2-K b and H2-D b , ocular dominance (OD) plasticity is enhanced. Mice lacking PirB, an MHCI receptor, have a similar phenotype. H2-K b and H2-D b are expressed not only in visual cortex, but also in lateral geniculate nucleus (LGN), where protein localization correlates strongly with synaptic markers and complement protein C1q. In K b D bÀ/À mice, developmental refinement of retinogeniculate projections is impaired, similar to C1q À/À mice. These phenotypes in K b D bÀ/À mice are strikingly similar to those in b2 m À/À TAP1 À/À mice, which lack cell surface expression of all MHCIs, implying that H2-K b and H2-D b can account for observed changes in synapse plasticity. H2-K b and H2-D b ligands, signaling via neuronal MHCI receptors, may enable activity-dependent remodeling of brain circuits during developmental critical periods.
Aneuploid neurons populate the normal adult brain, but the cause and the consequence of chromosom... more Aneuploid neurons populate the normal adult brain, but the cause and the consequence of chromosome abnormalities in the CNS are poorly defined. In the adult cerebral cortex of three genetic mutants, one of which is a mouse model of the human neurodegenerative disease ataxia-telangiectasia (A-T), we observed divergent levels of sex chromosome (XY) aneuploidy. Although both A-T mutated (Atm)-and transformation related protein 53 (Trp53)-dependent mechanisms are thought to clear newly postmitotic neurons with chromosome abnormalities, we found a 38% increase in the prevalence of XY aneuploidy in the adult Atm Ϫ/Ϫ cerebral cortex and a dramatic 78% decrease in Trp53 Ϫ/Ϫ mutant mice. A similar 43% decrease in adult XY aneuploidy was observed in DNA repair-deficient Xrcc5 Ϫ/Ϫ mutants. Additional investigation found an elevated incidence of aneuploid embryonic neural progenitor cells (NPCs) in all three mutants, but elevated apoptosis, a likely fate of embryonic NPCs with severe chromosome abnormalities, was observed only in Xrcc5 Ϫ/Ϫ mutants. These data lend increasing support to the hypothesis that hereditary mutations such as ATM-deficiency, which render abnormal cells resistant to developmental clearance, can lead to late-manifesting human neurological disorders.
A basic assumption about the normal nervous system is that its neurons possess identical genomes.... more A basic assumption about the normal nervous system is that its neurons possess identical genomes. Here we present direct evidence for genomic variability, manifested as chromosomal aneuploidy, among developing and mature neurons. Analysis of mouse embryonic cerebral cortical neuroblasts in situ detected lagging chromosomes during mitosis, suggesting the normal generation of aneuploidy in these somatic cells. Spectral karyotype analysis identified Ϸ33% of neuroblasts as aneuploid. Most cells lacked one chromosome, whereas others showed hyperploidy, monosomy, and͞or trisomy. The prevalence of aneuploidy was reduced by culturing cortical explants in medium containing fibroblast growth factor 2. Interphase fluorescence in situ hybridization on embryonic cortical cells supported the rate of aneuploidy observed by spectral karyotyping and detected aneuploidy in adult neurons. Our results demonstrate that genomes of developing and adult neurons can be different at the level of whole chromosomes.
A balance between inductive and repressive signals determines optimal flowering time for successf... more A balance between inductive and repressive signals determines optimal flowering time for successful reproduction in seasonal environments (28, 29). Our data demonstrate the importance of the repressors SVP, FLM-b, and FLC, which affect flowering at different but partially overlapping temperature ranges (fig. S19). However, we cannot exclude the possibility that the importance of SVP and FLM-b may not extend to Arabidopsis winter annual accessions. At lower temperatures, increased SVP protein interacts with FLM-b to repress flowering by direct binding to downstream targets. At higher temperatures, SVP protein levels decline, allowing expression of the downstream target genes and enabling flowering at that temperature. We propose that repressive activity of SVP requires FLM-b in the same complex and that SVP protein stability modulates the abundance of the SVP-FLM-b repressor complex to regulate ambient temperature-responsive flowering. SVP-like proteins have conserved functions across plant species (30, 31); therefore, control of SVP-FLM-b repressor complex abundance could be a general strategy for plants to adjust the balance of inductive and repressive signals under fluctuating temperature conditions.
Author contributions: M.J.M., Y.H.H., and C.J.S. designed research; M.J.M., Y.H.H., and A.D. perf... more Author contributions: M.J.M., Y.H.H., and C.J.S. designed research; M.J.M., Y.H.H., and A.D. performed research; M.J.M. contributed new reagents/analytic tools; M.J.M., Y.H.H., and C.J.S. analyzed data; and M.J.M., Y.H.H., and C.J.S. wrote the paper. The authors declare no conflict of interest. 1 M.J.M. and Y.H.H. contributed equally to this work.
Background: Existing quantitative models of mouse cerebral cortical development are not fully con... more Background: Existing quantitative models of mouse cerebral cortical development are not fully constrained by experimental data.
Major histocompatibility complex class I (MHCI) genes were discovered unexpectedly in healthy CNS... more Major histocompatibility complex class I (MHCI) genes were discovered unexpectedly in healthy CNS neurons in a screen for genes regulated by neural activity. In mice lacking just 2 of the 50+ MHCI genes H2-K b and H2-D b , ocular dominance (OD) plasticity is enhanced. Mice lacking PirB, an MHCI receptor, have a similar phenotype. H2-K b and H2-D b are expressed not only in visual cortex, but also in lateral geniculate nucleus (LGN), where protein localization correlates strongly with synaptic markers and complement protein C1q. In K b D bÀ/À mice, developmental refinement of retinogeniculate projections is impaired, similar to C1q À/À mice. These phenotypes in K b D bÀ/À mice are strikingly similar to those in b2 m À/À TAP1 À/À mice, which lack cell surface expression of all MHCIs, implying that H2-K b and H2-D b can account for observed changes in synapse plasticity. H2-K b and H2-D b ligands, signaling via neuronal MHCI receptors, may enable activity-dependent remodeling of brain circuits during developmental critical periods.
Aneuploid neurons populate the normal adult brain, but the cause and the consequence of chromosom... more Aneuploid neurons populate the normal adult brain, but the cause and the consequence of chromosome abnormalities in the CNS are poorly defined. In the adult cerebral cortex of three genetic mutants, one of which is a mouse model of the human neurodegenerative disease ataxia-telangiectasia (A-T), we observed divergent levels of sex chromosome (XY) aneuploidy. Although both A-T mutated (Atm)-and transformation related protein 53 (Trp53)-dependent mechanisms are thought to clear newly postmitotic neurons with chromosome abnormalities, we found a 38% increase in the prevalence of XY aneuploidy in the adult Atm Ϫ/Ϫ cerebral cortex and a dramatic 78% decrease in Trp53 Ϫ/Ϫ mutant mice. A similar 43% decrease in adult XY aneuploidy was observed in DNA repair-deficient Xrcc5 Ϫ/Ϫ mutants. Additional investigation found an elevated incidence of aneuploid embryonic neural progenitor cells (NPCs) in all three mutants, but elevated apoptosis, a likely fate of embryonic NPCs with severe chromosome abnormalities, was observed only in Xrcc5 Ϫ/Ϫ mutants. These data lend increasing support to the hypothesis that hereditary mutations such as ATM-deficiency, which render abnormal cells resistant to developmental clearance, can lead to late-manifesting human neurological disorders.
A basic assumption about the normal nervous system is that its neurons possess identical genomes.... more A basic assumption about the normal nervous system is that its neurons possess identical genomes. Here we present direct evidence for genomic variability, manifested as chromosomal aneuploidy, among developing and mature neurons. Analysis of mouse embryonic cerebral cortical neuroblasts in situ detected lagging chromosomes during mitosis, suggesting the normal generation of aneuploidy in these somatic cells. Spectral karyotype analysis identified Ϸ33% of neuroblasts as aneuploid. Most cells lacked one chromosome, whereas others showed hyperploidy, monosomy, and͞or trisomy. The prevalence of aneuploidy was reduced by culturing cortical explants in medium containing fibroblast growth factor 2. Interphase fluorescence in situ hybridization on embryonic cortical cells supported the rate of aneuploidy observed by spectral karyotyping and detected aneuploidy in adult neurons. Our results demonstrate that genomes of developing and adult neurons can be different at the level of whole chromosomes.
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Papers by Mike McConnell