A loss-of-function NUAK2 mutation in humans causes anencephaly due to impaired Hippo-YAP signaling

Abstract

Failure of neural tube closure during embryonic development can result in anencephaly, one of the most common birth defects in humans. A family with recurrent anencephalic fetuses was investigated to understand its etiology and pathogenesis. Exome sequencing revealed a recessive germline 21-bp in-frame deletion in NUAK2 segregating with the disease. In vitro kinase assays demonstrated that the 7–amino acid truncation in NUAK2, a serine/threonine kinase, completely abrogated its catalytic activity. Patient-derived disease models including neural progenitor cells and cerebral organoids showed that loss of NUAK2 activity led to decreased Hippo signaling via cytoplasmic YAP retention. In neural tube–like structures, endogenous NUAK2 colocalized apically with the actomyosin network, which was disrupted in patient cells, causing impaired nucleokinesis and apical constriction. Our results establish NUAK2 as an indispensable kinase for brain development in humans and suggest that a NUAK2-Hippo signaling axis regulates cytoskeletal processes that govern cell shape during neural tube closure.

NUAK2 and RCan2 participate in the p53 mutant pro-tumorigenic network

“…NUAK2 is a serine/threonine kinase, belonging to the family of AMPK, whose mutations are associated to congenital severe neurodevelopmental defects [ 71 ], although it is rarely observed mutated in cancer (Fig. 2 a).…”

Neuronal Hippo signaling: From development to diseases

“…Mutations in YAP1 also leads to congenital malformations during human brain development like orofacial clefting and intellectual disabilities (Williamson et al., 2014). A recent study investigating the significance of Hippo signaling during Drosophila brain development has illustrated that loss of Sd, a core member of Hippo pathway, can also lead to developmental deformities in the brain by virtue of abnormal neural expansion, as exemplified by their reduced cognitive performance (Bonnard et al., 2020). Reduced activity of Hippo components like Tead2 and PP2AC α has been implicated in mammalian neural tube defects and cerebral atrophy, respectively (Kaneko et al., 2007; Yu et al., 2016).…”

“…Periventricular nodular heterotopia is a form of cortical malformation which is frequently reported to be a consequence of insufficiency in several Hippo pathway‐associated genes like FILAMIN A, FAT4, DCHS1, and MOB2 (Cappello et al., 2013; Fox et al., 1998; O'Neill et al., 2018). A recent study has shown that loss‐of‐functional mutation in NUAK2 leads to reduced Hippo signaling via cytoplasmic YAP retention, which is turn results in anencephaly, one of the most common birth defects in humans arising from failure of neural tube closure during embryonic development (Bonnard et al., 2020). In the absence of NF2, there is an elevated YAP1 activity in the NPCs, which disrupt the formation of guidepost cells and results in dysplasia of the corpus callosum (Lavado et al., 2014).…”

NUAK1 and NUAK2 Fine-Tune TGF-β Signaling

“…NUAK1 has also been shown to be able to phosphorylate LATS1 [24], but whether NUAK1 exerts a similar or opposing function to NUAK2 on Hippo pathway signaling remains elusive. Recently, NUAK2 and the Hippo system have been shown to be of high relevance to a crucial stage in development of the human central nervous system: namely, the closing of the neural tube during embryogenesis [47]. Defects in closing the neural tube lead to a developmental brain defect called anencephaly: the absence of a large portion of the brain.…”