Dido mutations trigger perinatal death and generate brain abnormalities and behavioral alterations in surviving adult mice

Abstract

Nearly all vertebrate cells have a single cilium protruding from their surface. This threadlike organelle, once considered vestigial, is now seen as a pivotal element for detection of extracellular signals that trigger crucial morphogenetic pathways. We recently proposed a role for Dido3, the main product of the death inducerobliterator (dido) gene, in histone deacetylase 6 delivery to the primary cilium [Sánchez de Diego A, et al. (2014) Nat Commun 5:3500]. Here we used mice that express truncated forms of Dido proteins to determine the link with cilium-associated disorders. We describe dido mutant mice with high incidence of perinatal lethality and distinct neurodevelopmental, morphogenetic, and metabolic alterations. The anatomical abnormalities were related to brain and orofacial development, consistent with the known roles of primary cilia in brain patterning, hydrocephalus incidence, and cleft palate. Mutant mice that reached adulthood showed reduced life expectancy, brain malformations including hippocampus hypoplasia and agenesis of corpus callosum, as well as neuromuscular and behavioral alterations. These mice can be considered a model for the study of ciliopathies and provide information for assessing diagnosis and therapy of genetic disorders linked to the deregulation of primary cilia.ciliopathies | brain patterning | perinatal lethality

DIDO as a Switchboard that Regulates Self-Renewal and Differentiation in Embryonic Stem Cells

“…In vivo differentiation can be rescued by crossing Dido3ΔCT with the DidoΔNT mutant. These double mutants overcome embryonic lethality, although the mice suffer high perinatal mortality and neurodevelopmental, morphogenetic, and metabolic alterations ( Villares et al., 2015 ).…”

DIDO3 acts at the interface of RNAPII transcription and chromatin structure regulation

“…Previous sequence similarity searches of Dido1 have proposed its role in chromatin stability, transcriptional regulation and cancer (3,6). But additional experimental results accumulated over years, from our laboratory and others, support the proposed roles for Dido1 as well as raise new hypotheses (4,5,7,8,20,(56)(57)(58). It is also known that aberrant chromatin architecture causes transcriptional dysregulation, which is largely associated with cancer development and progression.…”

“…Besides, Setd5 gene-loss in mice lead to abnormal transcription with impaired RNA maturation and detrimental effects on splicing, and Setd5 haploinsufficiency impaired the proliferation of neural progenitors and result in behavioural deficits in mice (71). RNA-seq of DIDO3ΔE16 ESC identified a downregulation of Setd5 (Table 1), and coincidentally, DIDO3ΔE16 mutant produced splicing defects (58), and generated brain abnormalities and behavioural alterations in adult mice (57).…”

The SPOC domain is a phosphoserine binding module that bridges transcription machinery with co- and post-transcriptional regulators

“…Given that both PHF3 and DIDO bind to the same CTD phosphomark, it is conceivable that they might either bind to the elongation complex simultaneously and exercise synergistic functions or that their binding might be mutually exclusive and they compete for Pol II binding. Given their important roles in neuronal development 5, 9 they might also act redundantly. While genomic localization of PHF3 is largely dependent on the SPOC domain, DIDO PHD, in contrast to PHF3 PHD, binds to H3K4me3 histone marks and can thus bind chromatin independently of SPOC 39, 40 .…”