11/20/2022 0 Comments Organized trio activation keyG and H, lamination defects of the hippocampus in Trio mutant mice. The mitral cell layer ( MCL) is clearly visible in the control mice ( arrowheads) but cannot be distinguished from the internal granule cell layer in the mutant mice. E and F, hematoxylin and eosin-stained coronal sections of the olfactory bulbs of P21 mice. C and D, Nissl-stained sagittal sections show a reduced size of the mutant olfactory bulb and an enlarged rostral migratory stream ( RMS, arrowheads) at P0.5. Few mutants could survive for 3 weeks with severe ataxia, retarded growth, and smaller brain size. B, 90% of mutant mice died within 24 h after birth without sucking milk ( arrowhead, control stomach filled with milk). The probes used for Southern blot analysis are shown as solid blue bars, and the locations of PCR primers ( a–d) are for screening homologous recombination ( green arrows). Mice containing the floxed allele were crossed with Nestin-Cre ( tg) mice to generate Trio + /flox Nestin-Cre and Trio flox/flox Nestin-Cre mice. The first loxP site ( red arrowheads) was targeted downstream of exon 25. The 11.5-kb genomic DNA fragment containing Trio exons 22–25 was subcloned from 129/sv BAC. A, schematic representation of Trio knock-out strategy specific to the nervous system. Targeted disruption of the Trio gene in the nervous system. Trio may serve as a signal integrator decoding extrinsic signals to Rho GTPases for cytoskeleton organization. These results suggest that Trio may be a key signal module for the orchestrated regulation of neuronal migration and morphogenesis during cerebellar development. Trio deletion caused down-regulation of the activation of Rac1, RhoA, and Cdc42, and mutant granule cells appeared to be unresponsive to neurite growth-promoting molecules such as Netrin-1 and Semaphorin 6A. Trio-deficient granule cells showed reduced extension of neurites and highly branched and misguided processes with perturbed stabilization of actin and microtubules. Mutant cerebella had no granule cells in the internal granule cell layer due to aberrant granule cell migration as well as abnormal neurite growth. Knock-out mice showed defective cerebella and severe signs of ataxia. We established and analyzed mice with neural-specific knock-out of Trio, a guanine nucleotide exchange factor with multiple guanine nucleotide exchange factor domains. Orchestrated regulation of neuronal migration and morphogenesis is critical for neuronal development and establishment of functional circuits, but its regulatory mechanism is incompletely defined.
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