Neural tube closure requires the endocytic receptor Lrp2 and its functional interaction with intracellular scaffolds.

Pathogenic mutations in the endocytic receptor LRP2 in humans are associated with severe neural tube closure defects (NTDs) such as anencephaly and spina bifida. Here, we have combined analysis of neural tube closure in mouse and in the African Clawed Frog Xenopus laevis to elucidate the etiology of Lrp2-related NTDs. Lrp2 loss of function impaired neuroepithelial morphogenesis, culminating in NTDs that impeded anterior neural plate folding and neural tube closure in both model organisms. Loss of Lrp2 severely affected apical constriction as well as proper localization of the core planar cell polarity (PCP) protein Vangl2, demonstrating a highly conserved role of the receptor in these processes, which are essential for neural tube formation. In addition, we identified a novel functional interaction of Lrp2 with the intracellular adaptor proteins Shroom3 and Gipc1 in the developing forebrain. Our data suggest that, during neurulation, motifs within the intracellular domain of Lrp2 function as a hub that orchestrates endocytic membrane removal for efficient apical constriction, as well as PCP component trafficking in a temporospatial manner.

Identification of disease-relevant modulators of the SHH pathway in the developing brain.

Pathogenic gene variants in humans that affect the sonic hedgehog (SHH) pathway lead to severe brain malformations with variable penetrance due to unknown modifier genes. To identify such modifiers, we established novel congenic mouse models. LRP2-deficient C57BL/6N mice suffer from heart outflow tract defects and holoprosencephaly caused by impaired SHH activity. These defects are fully rescued on a FVB/N background, indicating a strong influence of modifier genes. Applying comparative transcriptomics, we identified Pttg1 and Ulk4 as candidate modifiers upregulated in the rescue strain. Functional analyses showed that ULK4 and PTTG1, both microtubule-associated proteins, are positive regulators of SHH signaling, rendering the pathway more resilient to disturbances. In addition, we characterized ULK4 and PTTG1 as previously unidentified components of primary cilia in the neuroepithelium. The identification of genes that powerfully modulate the penetrance of genetic disturbances affecting the brain and heart is likely relevant to understanding the variability in human congenital disorders.

Interplay between sex determination cascade and major signaling pathways during Drosophila eye development: Perspectives for future research.

Understanding molecular mechanisms of sexually dimorphic organ growth is a fundamental problem of developmental biology. Recent quantitative studies showed that the Drosophila compound eye is a convenient model to study the determination of the final organ size. In Drosophila, females have larger eyes than males and this is evident even after correction for the larger body size. Moreover, female eyes include more ommatidia (photosensitive units) than male eyes and this difference is specified at the third larval instar in the eye primordia called eye imaginal discs. This may result in different visual capabilities between the two sexes and have behavioral consequences. Despite growing evidence on the genetic bases of eye size variation between different Drosophila species and strains, mechanisms responsible for within-species sexual dimorphism still remain elusive. Here, we discuss a presumptive crosstalk between the sex determination cascade and major signaling pathways during dimorphic eye development. Male- and female-specific isoforms of Doublesex (Dsx) protein are known to control sex-specific differentiation in the somatic tissues. However, no data on Dsx function during eye disc growth and patterning are currently available. Remarkably, Sex lethal (Sxl), the sex determination switch protein, was shown to directly affect Hedgehog (Hh) and Notch (N) signaling in the Drosophila wing disc. The similarity of signaling pathways involved in the wing and eye disc growth suggests that Sxl might be integrated into regulation of eye development. Dsx role in the eye disc requires further investigation. We discuss currently available data on sex-biased gene expression in the Drosophila eye and highlight perspectives for future studies.