Cortical hypoplasia and ventriculomegaly of p73‐deficient mice: Developmental and adult analysis

Medina-Bolívar, Carolina; González‐Arnay, Emilio; Talos, Flaminia; González‐Gómez, Miriam; Moll, Ute M.; Meyer, Gundela

doi:10.1002/cne.23556

Cited by 22 publications

(35 citation statements)

References 48 publications

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“…We also noted a lack of MCCs in the ependymal cells (data not shown). It was recently reported that p73 is strongly expressed in murine ciliated ependymal cells and is required for their survival (Medina-Bolivar et al, 2014). p73 protein expression appeared nuclear by IF and was detected in the epithelium of *α-tubulin-positive tissues in p73+/+ animals (Figure 1A).…”

Section: Resultsmentioning

confidence: 99%

p73 Is Required for Multiciliogenesis and Regulates the Foxj1-Associated Gene Network

et al. 2016

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Summary We report that p73 is expressed in multiciliated cells (MCCs), is required for MCC differentiation, and directly regulates transcriptional modulators of multiciliogenesis. Loss of ciliary biogenesis provides a unifying mechanism for many phenotypes observed in p73 knockout mice including hydrocephalus, hippocampal dysgenesis, sterility and chronic inflammation/infection of lung, middle ear and sinus. Through p73 and p63 ChIP-seq using murine tracheal cells, we identified over 100 putative p73 target genes that regulate MCC differentiation and homeostasis. We validated Foxj1, a transcriptional regulator of multiciliogenesis, and many other cilia-associated genes as direct target genes of p73 and p63. We show p73 and p63 are co-expressed in a subset of basal cells, and suggest that p73 ‘marks’ these cells for MCC differentiation. In sum, p73 is essential for MCC differentiation, functions as a critical regulator of a transcriptome required for MCC differentiation and, like p63, has an essential role in development of tissues.

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Section: Resultsmentioning

confidence: 99%

p73 Is Required for Multiciliogenesis and Regulates the Foxj1-Associated Gene Network

et al. 2016

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“…; Medina‐Bolívar et al. ). While the p73KO neocortex has a variety of rather mild anatomical defects and an important hydrocephaly, the dominant malformation is the severe hippocampal dysgenesis.…”

Section: Introductionmentioning

confidence: 98%

“…in brain development (Meyer, ; Medina‐Bolívar et al. ; Niklison‐Chirou et al. ), ciliogenesis (Nemajerova et al.…”

Section: Introductionmentioning

confidence: 99%

Cajal‐Retzius neurons are required for the development of the human hippocampal fissure

et al. 2019

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Cajal-Retzius neurons (CRN) are the main source of Reelin in the marginal zone of the developing neocortex and hippocampus (HC). They also express the transcription factor p73 and are complemented by laterappearing GABAergic Reelin + interneurons. The human dorsal HC forms at gestational week 10 (GW10), when it develops a rudimentary Ammonic plate and incipient dentate migration, although the dorsal hippocampal fissure (HF) remains shallow and contains few CRN. The dorsal HC transforms into the indusium griseum (IG), concurrently with the rostro-caudal appearance of the corpus callosum, by GW14-17. Dorsal and ventral HC merge at the site of the former caudal hem, which is located at the level of the future atrium of the lateral ventricle and closely connected with the choroid plexus. The ventral HC forms at GW11 in the temporal lobe. The ventral HF is wide open at GW14-16 and densely populated by large numbers of CRNs. These are in intimate contact with the meninges and meningeal blood vessels, suggesting signalling through diverse pathways. At GW17, the fissure deepens and begins to fuse, although it is still marked by p73/Reelin + CRNs. The p73KO mouse illustrates the importance of p73 in CRN for HF formation. In the mutant, Tbr1/Reelin + CRNs are born in the hem but do not leave it and subsequently disappear, so that the mutant cortex and HC lack CRN from the onset of corticogenesis. The HF is absent, which leads to profound architectonic alterations of the HC. To determine which p73 isoform is important for HF formation, isoform-specific TAp73-and DeltaNp73deficient embryonic and early postnatal mice were examined. In both mutants, the number of CRNs was reduced, but each of their phenotypes was much milder than in the global p73KO mutant missing both isoforms. In the TAp73KO mice, the HF of the dorsal HC failed to form, but was present in the ventral HC. In the DeltaNp73KO mice, the HC had a mild patterning defect along with a shorter HF. Complex interactions between both isoforms in CRNs may contribute to their crucial activity in the developing brain.Sections were deparaffinized, hydrated, and boiled in 10 mM citrate buffer (pH 6) for 20 min for antigen retrieval, rinsed in Trisbuffered saline (TBS, pH 7.6, 0.05 M), and incubated in the primary antibodies overnight in a humid chamber. After rinsing, they were incubated in the corresponding biotinylated secondary antibodies (rabbit anti-mouse IgG or goat anti-rabbit IgG; Dako, Glostrup, Denmark), diluted at 1 : 200 in TBS, followed by incubation with avidin-biotin complex (ABC, DAKO) in TBS. Bound peroxidase was

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“…The latter is thought to be caused by an unspecified immune defect (Yang et al 2000). Interestingly, multiciliated ependymal cells that line ventricles and generate cerebrospinal fluid flow express p73, and p73 knockout ependyma displays impaired ciliogenesis (Medina-Bolivar et al 2014;Gonzalez-Cano et al 2015). While p73 knockout mice have severe hydrocephalus, isoform-specific knockout brains show milder discrete cortical phenotypes (Yang et al 2000;Tomasini et al 2008;Tissir et al 2009).…”

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confidence: 99%

TAp73 is a central transcriptional regulator of airway multiciliogenesis

Krämer²,

et al. 2016

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Motile multiciliated cells (MCCs) have critical roles in respiratory health and disease and are essential for cleaning inhaled pollutants and pathogens from airways. Despite their significance for human disease, the transcriptional control that governs multiciliogenesis remains poorly understood. Here we identify TP73, a p53 homolog, as governing the program for airway multiciliogenesis. Mice with TP73 deficiency suffer from chronic respiratory tract infections due to profound defects in ciliogenesis and complete loss of mucociliary clearance. Organotypic airway cultures pinpoint TAp73 as necessary and sufficient for basal body docking, axonemal extension, and motility during the differentiation of MCC progenitors. Mechanistically, cross-species genomic analyses and complete ciliary rescue of knockout MCCs identify TAp73 as the conserved central transcriptional integrator of multiciliogenesis. TAp73 directly activates the key regulators FoxJ1, Rfx2, Rfx3, and miR34bc plus nearly 50 structural and functional ciliary genes, some of which are associated with human ciliopathies. Our results position TAp73 as a novel central regulator of MCC differentiation.

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Cortical hypoplasia and ventriculomegaly of p73‐deficient mice: Developmental and adult analysis

Cited by 22 publications

References 48 publications

p73 Is Required for Multiciliogenesis and Regulates the Foxj1-Associated Gene Network

p73 Is Required for Multiciliogenesis and Regulates the Foxj1-Associated Gene Network

Cajal‐Retzius neurons are required for the development of the human hippocampal fissure

TAp73 is a central transcriptional regulator of airway multiciliogenesis

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