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.

Trajectory of rich club properties in structural brain networks.

Many organizational principles of structural brain networks are established before birth and undergo considerable developmental changes afterwards. These include the topologically central hub regions and a densely connected rich club. While several studies have mapped developmental trajectories of brain connectivity and brain network organization across childhood and adolescence, comparatively little is known about subsequent development over the course of the lifespan. Here, we present a cross-sectional analysis of structural brain network development in N = 8066 participants aged 5-80 years. Across all brain regions, structural connectivity strength followed an "inverted-U"-shaped trajectory with vertex in the early 30s. Connectivity strength of hub regions showed a similar trajectory and the identity of hub regions remained stable across all age groups. While connectivity strength declined with advancing age, the organization of hub regions into a rich club did not only remain intact but became more pronounced, presumingly through a selected sparing of relevant connections from age-related connectivity loss. The stability of rich club organization in the face of overall age-related decline is consistent with a "first come, last served" model of neurodevelopment, where the first principles to develop are the last to decline with age. Rich club organization has been shown to be highly beneficial for communicability and higher cognition. A resilient rich club might thus be protective of a functional loss in late adulthood and represent a neural reserve to sustain cognitive functioning in the aging brain.

Molecular identity of proprioceptor subtypes innervating different muscle groups in mice.

The precise execution of coordinated movements depends on proprioception, the sense of body position in space. However, the molecular underpinnings of proprioceptive neuron subtype identities are not fully understood. Here we used a single-cell transcriptomic approach to define mouse proprioceptor subtypes according to the identity of the muscle they innervate. We identified and validated molecular signatures associated with proprioceptors innervating back (Tox, Epha3), abdominal (C1ql2), and hindlimb (Gabrg1, Efna5) muscles. We also found that proprioceptor muscle identity precedes acquisition of receptor character and comprise programs controlling wiring specificity. These findings indicate that muscle-type identity is a fundamental aspect of proprioceptor subtype differentiation that is acquired during early development and includes molecular programs involved in the control of muscle target specificity.