Myotonic dystrophy (Dystrophia Myotonica; DM) is the most common adult-onset muscular dystrophy and its brain symptoms seriously affect patients’ quality of life. It is caused by extended (CTG) n expansions at 3′-UTR of DMPK gene (DM type 1, DM1) or (CCTG) n repeats in the intron 1 of CNBP gene (DM type 2, DM2) and the sequestration of Muscleblind-like (MBNL) family proteins by transcribed (CUG) n RNA hairpin is the main pathogenic mechanism for DM. The MBNL proteins are splicing factors regulating posttranscriptional RNA during development. Previously, Mbnl knockout (KO) mouse lines showed molecular and phenotypic evidence that recapitulate DM brains, however, detailed morphological study has not yet been accomplished. In our studies, control ( Mbnl1 +/+ ; Mbnl2 cond/cond ; Nestin-Cre −/− ), Mbnl2 conditional KO (2KO, Mbnl1 +/+ ; Mbnl2 cond/cond ; Nestin-Cre +/− ) and Mbnl1/2 double KO (DKO, Mbnl1 ΔE3/ΔE3 ; Mbnl2 cond/cond ; Nestin-Cre +/− ) mice were generated by crossing three individual lines. Immunohistochemistry for evaluating density and distribution of cortical neurons; Golgi staining for depicting the dendrites/dendritic spines; and electron microscopy for analyzing postsynaptic ultrastructure were performed. We found distributional defects in cortical neurons, reduction in dendritic complexity, immature dendritic spines and alterations of postsynaptic densities (PSDs) in the mutants. In conclusion, loss of function of Mbnl1/2 caused fundamental defects affecting neuronal distribution, dendritic morphology and postsynaptic architectures that are reminiscent of predominantly immature and fetal phenotypes in DM patients.
Vilse/Arhgap39 is a Rho GTPase activating protein (RhoGAP) and utilizes its WW domain to regulate Rac/Cdc42-dependent morphogenesis in Drosophila and murine hippocampal neurons. However, the function of Vilse in mammalian dendrite architecture and synaptic plasticity remained unclear. In the present study, we aimed to explore the possible role of Vilse in dendritic structure and synaptic function in the brain. Homozygous knockout of Vilse resulted in premature embryonic lethality in mice. Changes in dendritic complexity and spine density were noticed in hippocampal neurons of Camk2a-Cre mediated forebrain-specific Vilse knockout (VilseΔ/Δ) mice. VilseΔ/Δ mice displayed impaired spatial memory in water maze and Y-maze tests. Electrical stimulation in hippocampal CA1 region revealed that the synaptic transmission and plasticity were defected in VilseΔ/Δ mice. Collectively, our results demonstrate that Vilse is essential for embryonic development and required for spatial memory.
Connective tissue growth factor (CTGF) is a secreted extracellular matrix-associated protein, which play a role in regulating various cellular functions. Although the expression of CTGF has been reported in the cortical subplate, its function is still not clear. Thus, to explore the significance of CTGF in the brain, we created a forebrain-specific Ctgf knockout (Fb Ctgf KO) mouse model. By crossing Ctgf fl/fl mice with Emx1-Cre transgenic mice, in which the expression of Cre is prenatally initiated, the full length Ctgf is removed in the forebrain structures. In young adult (2–3 months old) Fb Ctgf KO mice, subplate markers such as Nurr1 and Cplx3 are still expressed in the cortical layer VIb; however, the density of the subplate neurons is increased. Interestingly, in these mutants, we found a reduced structural complexity in the subplate neurons. The distribution patterns of neurons and glial cells, examined by immunohistochemistry, are comparable between genotypes in the somatosensory cortex. However, increased densities of mature oligodendrocytes, but not immature ones, were noticed in the external capsule underneath the cortical layer VIb in young adult Fb Ctgf KO mice. The features of myelinated axons in the external capsule were then examined using electron microscopy. Unexpectedly, the thickness of the myelin sheath was reduced in middle-aged (>12 months old), but not young adult Fb Ctgf KO mice. Our results suggest a secretory function of the subplate neurons, through the release of CTGF, which regulates the density and dendritic branching of subplate neurons as well as the maturation and function of nearby oligodendrocytes in the white matter.
Connective tissue growth factor (CTGF) plays important roles in the development and regeneration of the connective tissue, yet its function in the nervous system is still not clear. CTGF is expressed in some distinct regions of the brain, including the dorsal endopiriform nucleus (DEPN) which has been recognized as an epileptogenic zone. We generated a forebrain-specific Ctgf knockout (FbCtgf KO) mouse line in which the expression of Ctgf in the DEPN is eliminated. In this study, we adopted a pentylenetetrazole (PTZ)-induced seizure model and found similar severity and latencies to death between FbCtgf KO and WT mice. Interestingly, there was a delay in the seizure reactions in the mutant mice. We further observed reduced c-fos expression subsequent to PTZ treatment in the KO mice, especially in the hippocampus. While the densities of astrocytes and microglia in the hippocampus were kept constant after acute PTZ treatment, microglial morphology was different between genotypes. Our present study demonstrated that in the FbCtgf KO mice, PTZ failed to increase neuronal activity and microglial response in the hippocampus. Our results suggested that inhibition of Ctgf function may have a therapeutic potential in preventing the pathophysiology of epilepsy.
PHRF1 is involved in transforming growth factor β (TGF-β) signaling to constrain the formation of acute promyelocytic leukemia (APL) in mouse APL models. PHRF1 also participates in modulating non-homologous end-joining. However, the role of PHRF1 in mammalian dendrite architecture and synaptic plasticity is unclear. Here, we investigated the role of PHRF1 in dendritic formation in the murine hippocampus using Camk2a promoter driven-iCre recombinase to conduct a PHRF1 conditional knockout, namely PHRF1Δ/Δ, in the forebrain region. PHRF1Δ/Δ mice developed normally, but exhibited anxiety-like behaviors and displayed defective spatial memory. Alterations of dendritic complexity in apical and basal dendrites of pyramidal neurons were noticed in PHRF1Δ/Δ mutants. Furthermore, electrical stimulation in the hippocampal CA1 region after the TGF-β1 treatment showed a reduced synaptic plasticity in PHRF1Δ/Δ mice. Immunoblotting analysis indicated that PHRF1 ablation affected the TGF-β signaling. Collectively, our results demonstrate that PHRF1 is important for the dendritic architecture and required for spatial memory formation in the hippocampus.
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