The overall goal of this proposal is to elucidate the mechanisms underlying the developmental defects leading
to cortical malformation by characterizing the fundamental antagonistic interactions between evolutionarily
conserved polarity complex proteins. Disruption of neuroepithelial structure causes abnormalities in neuronal
outputs and cortical malformation that lead to a spectrum of neurodevelopmental disorders, including
periventricular heterotopia (PH), microcephaly and ventriculomegaly. Asymmetrically distributed polarity
protein complexes are critical for establishing and maintaining polarized cellular architecture and for
determining unequal cell fate.
Two complexes (Crb/Pals1/Patj and Mupp1; Par3/Par6/aPKC), termed apical
polarity complex proteins, are localized at the apical side and one basal polarity complex (Lgl/DLG/Scb) is
located basolaterally. Despite its critical importance for cortical epithelial structure and progenitor cell division,
it is unclear whether a well-balanced interaction between them is required for cortical structure and
neurogenesis, and the cellular and molecular machinery that mediates their functional interaction is also poorly
understood. To identify their essential functional interactions and the underlying molecular mechanisms, we
have generated a cortical-specific Llgl1 mutant characterized by massive PH and a cortical-specific Crb2
mutant with ventriculomegaly. Remarkably, Crb1/2 loss drastically reduces heterotopia in the Llg1 mutant. It
has previously been shown that Llgl1 binds to myosin and regulates its activity, and that apical polarity
complex proteins aPKC and Crb2 can inhibit myosin activity. Importantly, because cellular tension and junction
defects are associated with the activation of mitogenic signals such as Yap/Taz transcription coactivator,
downstream effectors of the Hippo pathway, this antagonism may also be linked to abnormal proliferation that
produces the enlarged heterotopic cortex found in Llgl1 CKO. These observations lead us to hypothesize that
the antagonistic interaction between basal and apical polarity complexes is required to
establish/localize actomyosin at the apical junction and prevent activation of an abnormal Yap/Taz-
dependent mitogenic signal. To test this hypothesis, in Aim1 we will define the antagonistic relationship
between apical and basal complexes in cortical progenitor proliferation and junctional integrity by analyzing
mutant mice. In Aim2 we will delineate the mechanism(s) by which polarity complex proteins regulate junctional
integrity by investigating the antagonistic regulation of actomyosin. Lastly, in Aim3 we will determine whether
Yap-Taz regulate mitogenic signaling after polarity disruption. Our study will increase understanding of polarity
complex protein interactions in cortical progenitor cell division, which will provide new insights into the
pathogenesis of cortical malformation and ultimately a basis for novel treatments.