Abstract
Holoprosencephaly is a common developmental disorder in humans characterised by incomplete brain hemisphere separation and midface anomalies. The etiology of holoprosencephaly is heterogeneous with environmental and genetic causes, but for a majority of holoprosencephaly cases the genes associated with the pathogenesis could not be identified so far. Here we report the generation of knockout mice for the ubiquitin E3 ligase NOSIP. The loss of NOSIP in mice causes holoprosencephaly and facial anomalies including cleft lip/palate, cyclopia and facial midline clefting. By a mass spectrometry based protein interaction screen we identified NOSIP as a novel interaction partner of protein phosphatase PP2A. NOSIP mediates the monoubiquitination of the PP2A catalytic subunit and the loss of NOSIP results in an increase in PP2A activity in craniofacial tissue in NOSIP knockout mice. We conclude, that NOSIP is a critical modulator of brain and craniofacial development in mice and a candidate gene for holoprosencephaly in humans.
Highlights
The formation of the vertebrate head during embryonic development is a complex process requiring the co-ordinated behaviour of a variety of different cell types
In addition we found that the weight of NOSIP KO embryos was significantly reduced (Fig. 1E)
We found that the protein levels of both enzymes were unchanged in Mouse embryonic fibroblasts (MEFs) isolated from NOSIP KO embryos in comparison to WT (Fig. 6A)
Summary
The formation of the vertebrate head during embryonic development is a complex process requiring the co-ordinated behaviour of a variety of different cell types. To respond accurately to the cues of the developmental programme, it is essential that these cells receive and integrate extracellular signals and that their signal transduction is and tightly controlled [1, 2]. Perturbation of these processes can result in devastating congenital malformations. HPE is characterised by incomplete separation of the two cerebral hemispheres and a failure to define the midface. Depending on the degree of cerebral hemisphere separation, classical HPE is divided into three forms: alobar, semilobar and lobar HPE, associated with a continuous range of clinical manifestations. The identification of novel HPE-associated genes is crucial for further understanding of the signalling pathways involved in forebrain and craniofacial development and the pathogenesis of HPE [2, 4, 5]
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