Ultanir lab

Kinases and Brain Development Laboratory

: NDR family of kinases

NDR1/2

Nuclear Dbf2 Related (NDR) kinases NDR1 and NDR2 are part of the AGC group of serine/ threonine kinases and together with LATS1/2 form the NDR family of kinase. NDR1/2 and their orthologues play roles in cell polarization and morphogenesis and regulate neuronal dendrite development in flies, worms and mice.

We have previously identified direct substrates of NDR1 using a chemical genetic approach, which include membrane trafficking regulators (Ultanir et al, 2012, Neuron). We generated neuron-specific dual deletion of NDR1 and NDR2 in mice. This novel mouse model showed early-onset neurodegeneration in cortex and hippocampus, implicating NDR1/2 dependent signaling in neurodegeneration. This phenotype was present when NDR kinases were deleted in adult mice, proving their role in neuronal maintenance.

Proteomic and phosphoproteomic comparisons between Ndr1/2 knockout and control brains confirmed our earlier findings and expanded the list of NDR1/2 kinase substrates to multiple membrane trafficking regulators. We validated the endocytic protein Raph1/Lpd1, as a novel NDR1/2 substrate, and showed that NDR1/2 is required for endocytosis and membrane recycling.

In NDR1/2 knockout brains, we observed prominent accumulation of transferrin receptor (TfR), p62 and ubiquitinated proteins, indicative of a major impairment of protein homeostasis. Our result provides novel insight into the roles of NDR1/2 kinases in maintaining neuronal health (Rosianu et al, 2022, Life Science Alliance). 

LATS1/2 and YAP/TAZ

YAP1-gene fusions cause a subtype of pediatric ependymoma tumours. It was not clear if YAP1 activity is sufficient in causing ependymomas, or the fusion proteins are pathological. Using conditional knockout mouse models, we demonstrate that uncontrolled hyperactive YAP1/TAZ in radial glia derived neural precursor cells is sufficient for ependymoma-like tumour formation in mice.

We revealed HOPX, a transcription factor known to be consistently suppressed in malignancies, is increased in mouse YAP driven tumours. We showed that high HOPX expression differentiates YAP1-fusion subtype from the highly malignant RELA-fusion human ependymomas in tissue stainings (Eder et al, 2020, Nature Communications).

Our work supports the notion for subtype-specific care for ependymoma, YAP1-driven tumours being less malignant.