To examine the role of the p53 homolog p73 in brain development, we studied p73 Ϫ/Ϫ , p73 ϩ/Ϫ , E2F1 Ϫ/Ϫ , and reeler mutant mice. p73 in developing brain is expressed in Cajal-Retzius (CR) cells, the cortical hem, and the choroid plexus. p73-expressing CR cells are lost in p73 Ϫ/Ϫ embryos, although Reelin is faintly expressed in the marginal zone. Ectopic neurons in the p73 Ϫ/Ϫ preplate and cortical hem at embryonic day 12 implicate p73 in the early developmental program of the cortex; however, preplate partition and early cortical plate formation are not disturbed. Postnatal p73 Ϫ/Ϫ mice show a mild hypoplasia of the rostral cortex and a severely disrupted architecture of the posterior telencephalon. In the developing p73 Ϫ/Ϫ hippocampus, the most striking abnormality is the absence of the hippocampal fissure, suggesting a role of p73 in cortical folding. p73 ϩ/Ϫ mice have a less severe cortical phenotype; they display a dorsal shift of the entorhinal cortex and a reduced size of occipital and posterior temporal areas, which acquire entorhinal-like features such as Reelinpositive cells in layer II. CR cells appear unaffected by heterozygosity. We relate the malformations of the posterior pole in p73 mutant mice to alterations of p73 expression in the cortical hem and suggest that p73 forms part of an early signaling network that controls neocortical and archicortical regionalization. In mice deficient for the transcription factor E2F1, a main activator of the TAp73 (transactivating p73) isoform, we find a defect of the caudal cortical architecture resembling the p73 ϩ/Ϫ phenotype along with reduced TAp73 protein levels and propose that an E2F1-TAp73 dependent pathway is involved in cortical patterning.

Epilepsy and mental retardation, originally of unknown cause, are now known to result from many defects including cortical malformations, neuronal circuitry disorders and perturbations of neuronal communication and synapse function. Genetic approaches in combination with MRI and related imaging techniques continually allow a re-evaluation and better classification of these disorders. Here we review our current understanding of some of the primary defects involved, with insight from recent molecular biology advances, the study of mouse models and the results of neuropathology analyses. Through these studies the molecular determinants involved in the control of neuron number, neuronal migration, generation of cortical laminations and convolutions, integrity of the basement membrane at the pial surface, and the establishment of neuronal circuitry are being elucidated. We have attempted to integrate these results with the available data concerning, in particular, human brain development, and to emphasize the limitations in some cases of extrapolating from rodent models. Taking such species differences into account is clearly critical for understanding the pathophysiological mechanisms associated with these disorders.

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Background Apolipoprotein E (APOE) genotype is the main genetic risk factor for Alzheimer’s disease (AD). APOE ε2 haplotype is protective, APOE ε3 is neutral, and APOE Ɛ4 is associated with the highest risk to develop the disease. APOE highly is conserved in vertebrates, but homology between human and mouse sequence is low (73.4% for peptide and 78.7% for the genetic sequences). To better understand the contribution of each APOE allele to the pathophysiology of AD it is necessary to generate preclinical models that recapitulate the molecular and biochemical properties of this complex gene. Within ADAPTED (Alzheimer's Disease Apolipoprotein Pathology for Treatment Elucidation and Development) project we have generated and characterized human iPSC‐derived brain cells to fill this important gap. Method All ADAPTED isogenic iPSC‐lines were differentiated into clinically relevant cell types (neurons, astrocytes and microglia) that were characterized using unbiased methodologies (transcriptomics, metabolomics and proteomics) and functional assays such as neuronal activity, cytokine release and phagocytosis. We performed all possible comparisons across genotypes, and mostly focused on results that were replicated across the two sets. Result We prioritized the study of iPSC‐derived glial cells based on expression levels of apoE and their critical role in brain function and AD pathophysiology. Our strategy led to the identification of APOE allele‐specific molecular signatures and pathways that partially replicates clinical findings (e.g. inflammatory response and metabolic properties). Functional assays revealed genotype differences that were also replicated in different genetic backgrounds. Conclusion Systematic comparison of relevant cells types stratified by APOE genotypes revealed key signatures and mechanisms that have been associated to AD. Data generated from iPSC‐derived cells proves this model as a reliable tool to further study the human biology of APOE, providing one step further in our understanding of AD and the potential identification of more effective therapies. iPSC lines generated within ADAPTED are globally available to the scientific community via EBiSC repository.