PARD3 dysfunction in conjunction with dynamic HIPPO signaling drives cortical enlargement with massive heterotopia.

Proper organization and orderly mitosis of radial glial progenitors (RGPs) drive the formation of a laminated mammalian cortex in the correct size. However, the molecular underpinnings of the intricate process remain largely unclear. Here we show that RGP behavior and cortical development are controlled by temporally distinct actions of partitioning-defective 3 (PARD3) in concert with dynamic HIPPO signaling. RGPs lacking PARD3 exhibit developmental stage-dependent abnormal switches in division mode, resulting in an initial overproduction of RGPs located largely outside the ventricular zone at the expense of deep-layer neurons. Ectopically localized RGPs subsequently undergo accelerated and excessive neurogenesis, leading to the formation of an enlarged cortex with massive heterotopia and increased seizure susceptibility. Simultaneous removal of HIPPO pathway effectors Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) suppresses cortical enlargement and heterotopia formation. These results define a dynamic regulatory program of mammalian cortical development and highlight a progenitor origin of megalencephaly with ribbon heterotopia and epilepsy.

Assessing the translational value of pre-clinical studies for clinical response rate in oncology: an exploratory investigation of 42 FDA-approved small-molecule targeted anticancer drugs.

PURPOSE: To assess the translational value of anticancer preclinical models, we retrospectively investigated the relationships between preclinical data and clinical response rate for 42 small-molecule targeted anticancer drugs approved by the US FDA from 2001 to 2018. METHODS: For 42 FDA-approved drugs, relevant pre-clinical (IC50, mouse PK/efficacy) and clinical (overall response rates [ORR], PK) data were extracted from the public domain. Relationships were investigated overall and separately by mechanism of action and solid vs liquid tumors. Binomial-normal regression analysis was performed using R. RESULTS: A significant correlation was found between the ratio of free human average plasma concentration (hCave) at the approved clinical dose to biochemical IC50 and ORR for kinase inhibitors with solid tumor indications (KIST). We also identified that, for KIST, the ratios of (i) total and (ii) free human-to-mouse average plasma concentration at efficacious doses were correlated to ORR ((i) R2 = 0.72, n = 10; (ii) R2 = 0.78, n = 10)). CONCLUSION: Relationships were identified for ratios of efficacious clinical exposures to typical preclinical pharmacology data and ORR for KIST in this retrospective analysis. Although the obtained datasets are limited, the relationships demonstrate that a systemic exposure relative to established pre-clinical pharmacology experiments for an investigational KIST could be used as a reference to assess if desired efficacy could be achieved. This approach may assist selection of the recommended phase 2 dose (RP2D) of an investigational drug.

Progressive divisions of multipotent neural progenitors generate late-born chandelier cells in the neocortex.

Diverse γ-aminobutyric acid (GABA)-ergic interneurons provide different modes of inhibition to support circuit operation in the neocortex. However, the cellular and molecular mechanisms underlying the systematic generation of assorted neocortical interneurons remain largely unclear. Here we show that NKX2.1-expressing radial glial progenitors (RGPs) in the mouse embryonic ventral telencephalon divide progressively to generate distinct groups of interneurons, which occupy the neocortex in a time-dependent, early inside-out and late outside-in, manner. Notably, the late-born chandelier cells, one of the morphologically and physiologically highly distinguishable GABAergic interneurons, arise reliably from continuously dividing RGPs that produce non-chandelier cells initially. Selective removal of Partition defective 3, an evolutionarily conserved cell polarity protein, impairs RGP asymmetric cell division, resulting in premature depletion of RGPs towards the late embryonic stages and a consequent loss of chandelier cells. These results suggest that consecutive asymmetric divisions of multipotent RGPs generate diverse neocortical interneurons in a progressive manner.

Vascular Influence on Ventral Telencephalic Progenitors and Neocortical Interneuron Production.

The neocortex contains glutamatergic excitatory neurons and γ-aminobutyric acid (GABA)ergic inhibitory interneurons. Extensive studies have revealed substantial insights into excitatory neuron production. However, our knowledge of the generation of GABAergic interneurons remains limited. Here we show that periventricular blood vessels selectively influence neocortical interneuron progenitor behavior and neurogenesis. Distinct from those in the dorsal telencephalon, radial glial progenitors (RGPs) in the ventral telencephalon responsible for producing neocortical interneurons progressively grow radial glial fibers anchored to periventricular vessels. This progenitor-vessel association is robust and actively maintained as RGPs undergo interkinetic nuclear migration and divide at the ventricular zone surface. Disruption of this association by selective removal of INTEGRIN ß1 in RGPs leads to a decrease in progenitor division, a loss of PARVALBUMIN and SOMATOSTATIN-expressing interneurons, and defective synaptic inhibition in the neocortex. These results highlight a prominent interaction between RGPs and periventricular vessels important for proper production and function of neocortical interneurons.