Regulation of cerebral cortical neurogenesis by the Pax6 transcription factor

Understanding brain development remains a major challenge at the heart of understanding what makes us human. The neocortex, in evolutionary terms the newest part of the cerebral cortex, is the seat of higher cognitive functions. Its normal development requires the production, positioning and appropriate interconnection of very large numbers of both excitatory and inhibitory neurons. Pax6 is one of a relatively small group of transcription factors that exert high-level control of cortical development, and whose mutation or deletion from developing embryos causes major brain defects and a wide range of neurodevelopmental disorders. Pax6 is very highly conserved between primate and non-primate species, is expressed in a gradient throughout the developing cortex and is essential for normal corticogenesis. Our understanding of Pax6’s functions and the cellular processes that it regulates during mammalian cortical development has significantly advanced in the last decade, owing to the combined application of genetic and biochemical analyses. Here we review the functional importance of Pax6 in regulating cortical progenitor proliferation, neurogenesis, and formation of cortical layers and highlight important differences between rodents and primates. We also review the pathological effects of PAX6 mutations in human neurodevelopmental disorders. Finally, we discuss some aspects of Pax6’s molecular actions including its own complex transcriptional regulation, the distinct molecular functions of its splice variants and some of Pax6’s known direct targets which mediate its actions during cortical development

Bulletin of EEI Stats

In industrials process and many studies cases, state and output derivative variables can be easily modeled in reciprocal state space (RSS) form than the standard one. Formulation of stabilization problem with a guaranteed cost control using feedback principle for Lipschitz nonlinear systems (LNS) in RSS is presented in this brief. The asymptotic stability, using the proper Lyapunov functions of the closed-loop system, is guaranteed. The control design problem is guaranteed through a resolution of linear matrix inequalities (LMI) technique under certain lemmas and minimization of non-standard cost control. Experimental validation shows the good performances of the proposed method using real-time implementation (RTI) with a digital signal processing (DSP) device (Arduino MEGA 2560)

PIK3CA mutations in breast cancer: A Tunisian series.

BackgroundThe aim of this study was to analyze PIK3CA mutations in exons 9 and 20 in breast cancers (BCs) and their association with clinicopathological characteristics.MethodsMutational analysis of PIK3CA exon 9 and 20 was performed by Sanger sequencing in 54 primary BCs of Tunisian women. The associations of PIK3CA mutations with clinicopathological characteristics were analyzed.ResultsFifteen exon 9 and exon 20 PIK3CA variants were identified in 33/54 cases (61%). PIK3CA mutations including pathogenic (class 5/Tier I) or likely pathogenic (class 4/Tier II) occurred in 24/54 cases (44%): 17/24 cases (71%) in exon 9, 5/24 cases (21%) in exon 20 and 2/24 cases (8%) in both exons. Of these 24 cases, 18 (75%) carried at least one of the three hot spot mutations: E545K (in 8 cases), H1047R (in 4 cases), E542K (in 3 cases), E545K/E542K (in one case), E545K/H1047R (in one case) and P539R/H1047R (in one case). Pathogenic PIK3CA mutations were associated with negative lymph node status (p = 0.027). Age distribution, histological SBR tumor grading, estrogen and progesterone receptors, human epidermal growth factor receptor 2, and molecular classification were not correlated with PIK3CA mutations (p > 0.05).ConclusionThe frequency of somatic PIK3CA mutations in BCs of Tunisian women is slightly higher than that of BCs of Caucasian women and more observed in exon 9 than in exon 20. PIK3CA mutated status is associated with negative lymph node status. These data need to be confirmed in larger series

<i>PIK3CA</i> variant’s classification according to the American College of Medical Genetics and Genomics guidelines.

PIK3CA variant’s classification according to the American College of Medical Genetics and Genomics guidelines.</p

Prediction function and conservation of variants with unknown functions.

Prediction function and conservation of variants with unknown functions.</p

Association between PIK3CA mutations and clinicopathological characteristics of breast cancer.

Association between PIK3CA mutations and clinicopathological characteristics of breast cancer.</p

Summary of variants annotation using the reference sequence NM_006218.4 and classification according to ACMG.

Summary of variants annotation using the reference sequence NM_006218.4 and classification according to ACMG.</p

Fig 1 -

Electropherograms of the 15 PIK3CA variants identified in breast cancers (A) Known PIK3CA mutations (B) Novel variants. All sequences are in sense strand. Red rectangle box shows the position of the mutations. The major peak corresponds to the normal nucleotide and the minor peak corresponds to the mutant nucleotide. Altered nucleotide and amino acid positions and related codon substitution are shown of each corresponding sequence.</p

Primer sequences, annealing temperatures and product lengths.

Primer sequences, annealing temperatures and product lengths.</p