The Trp73 Mutant Mice: A Ciliopathy Model That Uncouples Ciliogenesis From Planar Cell Polarity

Abstract

p73 transcription factor belongs to one of the most important gene families in vertebrate biology, the p53-family. Trp73 gene, like the other family members, generates multiple isoforms named TA and DNp73, with different and, sometimes, antagonist functions. Although p73 shares many biological functions with p53, it also plays distinct roles during development. Trp73 null mice (p73KO from now on) show multiple phenotypes as gastrointestinal and cranial hemorrhages, rhinitis and severe central nervous system defects. Several groups, including ours, have revisited the apparently unrelated phenotypes observed in total p73KO and revealed a novel p73 function in the organization of ciliated epithelia in brain and trachea, but also an essential role as regulator of ependymal planar cell polarity. Unlike p73KO or TAp73KO mice, tumor-prone Trp53−/− mice (p53KO) do not present ependymal ciliary or planar cell polarity defects, indicating that regulation of ciliogenesis and PCP is a p73-specific function. Thus, loss of ciliary biogenesis and epithelial organization might be a common underlying cause of the diverse p73KO-phenotypes, highlighting Trp73 role as an architect of the epithelial tissue. In this review we would like to discuss the data regarding p73 role as regulator of ependymal cell ciliogenesis and PCP, supporting the view of the Trp73-mutant mice as a model that uncouples ciliogenesis from PCP and a possible model of human congenital hydrocephalus.

Transcriptional regulation of multiciliated cell differentiation

“…The TF p73 (encoded by TP73 and Trp73 in humans or mice) is a member of the p53 family that also includes p63, a marker of basal progenitor cells that give rise to MCCs in the airway [15]. Given its relationship to p53, one of the most well studied tumor suppressors, p73 was extensively studied in mice and was shown to cause a number of developmental phenotypes, many of which have been recently linked to defects in MCC differentiation [50]. The TP73 gene generates 2 major isoform groups via 2 promoters; the activating (TAp73) or an N-terminally truncated (DNp73) form lacking the transactivating domain.…”

“…P73 is induced by both GEMC1 and MCIDAS through their respective E2F4/5-DP1-containing complexes, although it remains unclear if MCIDAS also interacts with p73. P73 expression has been reported in p63+ basal cells and Radial Glial Cells (RGCs), that act as MCC progenitors in the airway and brain, respectively, suggesting an early role for p73 in MCC fate specification independent of GEMC1 or MCIDAS, although this remains controversial [50][51][52]54]. The requirement for p73 appears to also vary depending on the isoform, tissue and cell type.…”

“…Following their amplification, centrioles are transported to the apical surface in an actin-myosin dependent manner and the organization and attachment of the BBs takes place, regulated in part by ERK7, DVL1/2, CapZIP, CELSR2/3, WDR5, GTPases and the miR-34/449 family to ensure correct cilia function and integrity of the epithelium [19,37,50,99,[118][119][120][121][122][123][124][125][126]. While the details of transcriptional crosstalk with the cytoskeleton and PCP pathways remains to be fully elucidated, MYB, FOXJ1, p73 RFX2 and RFX3, all contribute to the regulation of genes that ensure correct BB migration and docking, axoneme outgrowth, and motility, as well as cilia beating in frogs and mice [61,65,66,105,123,[127][128][129].…”

p73 as a Tissue Architect

“…In these pinwheels, the EpCs are polarized within the plane of the tissue, a process that is known as PCP. This essential feature of animal tissues (Butler and Wallingford, 2017) makes feasible that EpCs coordinate cilia beating and direct the cerebrospinal fluid circulation; therefore, PCP disruption results in ciliopathies and hydrocephalus (Marques et al, 2019).…”

“…One of the most striking features of the Trp73 −/− mice is the complete lack of cytoarchitecture in the SVZ neurogenic niche (Gonzalez-Cano et al, 2016;Fuertes-Alvarez et al, 2018;Marques et al, 2019). TAp73, but not DNp73, is expressed in the EpCs and its precursors, the radial glia cells (Tissir et al, 2009;Hernández-Acosta et al, 2011;Medina-Bolívar et al, 2014;Fujitani et al, 2017), and it is essential for the ependymal cell assembly into neurogenic pinwheels (Gonzalez-Cano et al, 2016).…”