Kidney organoid research: current status and applications.

Organoids are being widely introduced as novel research models in multiple research fields. Human-induced pluripotent stem cells-derived kidney organoids became an indispensable tool to study human kidney development, model various diseases and infections leading to kidney damage, and offer a new route towards better drug development and validation, personalized drug screening, and regenerative medicine. In this review, we provide an update of the most recent developments in kidney organoid induction: their main goals, advantages, and shortcomings. We further discuss their current applications in providing modeling and treatment avenues to various kidney injuries, their use in genome-wide screening of kidney diseases, and the cell interactions occurring in these kidney structures.

DWnt4 and DWnt10 Regulate Morphogenesis and Arrangement of Columnar Units via Fz2/PCP Signaling in the Drosophila Brain.

Columns are structural and functional units of the brain. However, the mechanism of column formation remains unclear. The medulla of the fly visual center shares features with the mammalian cerebral cortex, such as columnar and layered structures, and provides a good opportunity to study the mechanisms of column formation. Column formation is initiated by three core neurons in the medulla, namely, Mi1, R8, and R7. The proper orientation of neurons is required for the orientation and arrangement of multiple columns. Their orientations may be under the control of planar cell polarity (PCP) signaling, because it is known to regulate the orientation of cells in two-dimensional tissue structures. In this study, we demonstrate that the ligands DWnt4 and DWnt10 expressed specifically in the ventral medulla and dorsal medulla, respectively, globally regulate the columnar arrangement and orientation of Mi1 and R8 terminals through Fz2/PCP signaling in a three-dimensional space.

Dscam1 establishes the columnar units through lineage-dependent repulsion between sister neurons in the fly brain.

The brain is organized morphologically and functionally into a columnar structure. According to the radial unit hypothesis, neurons from the same lineage form a radial unit that contributes to column formation. However, the molecular mechanisms that link neuronal lineage and column formation remain elusive. Here, we show that neurons from the same lineage project to different columns under control of Down syndrome cell adhesion molecule (Dscam) in the fly brain. Dscam1 is temporally expressed in newly born neuroblasts and is inherited by their daughter neurons. The transient transcription of Dscam1 in neuroblasts enables the expression of the same Dscam1 splice isoform within cells of the same lineage, causing lineage-dependent repulsion. In the absence of Dscam1 function, neurons from the same lineage project to the same column. When the splice diversity of Dscam1 is reduced, column formation is significantly compromised. Thus, Dscam1 controls column formation through lineage-dependent repulsion.

N-Cadherin Orchestrates Self-Organization of Neurons within a Columnar Unit in the Drosophila Medulla.

Columnar structure is a basic unit of the brain, but the mechanism underlying its development remains largely unknown. The medulla, the largest ganglion of the Drosophila melanogaster visual center, provides a unique opportunity to reveal the mechanisms of 3D organization of the columns. In this study, using N-cadherin (Ncad) as a marker, we reveal the donut-like columnar structures along the 2D layer in the larval medulla that evolves to form three distinct layers in pupal development. Column formation is initiated by three core neurons, R8, R7, and Mi1, which establish distinct concentric domains within a column. We demonstrate that Ncad-dependent relative adhesiveness of the core columnar neurons regulates their relative location within a column along a 2D layer in the larval medulla according to the differential adhesion hypothesis. We also propose the presence of mutual interactions among the three layers during formation of the 3D structures of the medulla columns.SIGNIFICANCE STATEMENT The columnar structure is a basic unit of the brain, but its developmental mechanism remains unknown. The medulla, the largest ganglion of the fly visual center, provides a unique opportunity to reveal the mechanisms of 3D organization of the columns. We reveal that column formation is initiated by three core neurons that establish distinct concentric domains within a column. We demonstrate the in vivo evidence of N-cadherin-dependent differential adhesion among the core columnar neurons within a column along a 2D layer in the larval medulla. The 2D larval columns evolve to form three distinct layers in the pupal medulla. We propose the presence of mutual interactions among the three layers during formation of the 3D structures of the medulla columns.

A population dynamics model of cell-cell adhesion incorporating population pressure and density saturation.

We discuss several continuum cell-cell adhesion models based on the underlying microscopic assumptions. We propose an improvement on these models leading to sharp fronts and intermingling invasion fronts between different cell type populations. The model is based on basic principles of localized repulsion and nonlocal attraction due to adhesion forces at the microscopic level. The new model is able to capture both qualitatively and quantitatively experiments by Katsunuma et al. (2016). We also review some of the applications of these models in other areas of tissue growth in developmental biology. We finally explore the resulting qualitative behavior due to cell-cell repulsion.

Temporal patterning of neurogenesis and neural wiring in the fly visual system.

During neural development, a wide variety of neurons are produced in a highly coordinated manner and form complex and highly coordinated neural circuits. Temporal patterning of neuron type specification plays very important roles in orchestrating the production and wiring of neurons. The fly visual system, which is composed of the retina and the optic lobe of the brain, is an outstanding model system to study temporal patterning and wiring of the nervous system. All of the components of the fly visual system are topographically connected, and each ommatidial unit in the retina corresponds to a columnar unit in the optic lobe. In the retina, the wave of differentiation follows the morphogenetic furrow, which progresses in a posterior-to-anterior direction. At the same time, differentiation of the optic lobe also accompanies the wave of differentiation or temporally coordinated neurogenesis. Thus, temporal patterning plays important roles in establishing topographic connections throughout the fly visual system. In this article, we review how neuronal differentiation and connectivity are orchestrated in the fly visual system by temporal patterning mechanisms.

Wnt Signaling Specifies Anteroposterior Progenitor Zone Identity in the Drosophila Visual Center.

UNLABELLED: During brain development, various types of neuronal populations are produced from different progenitor pools to produce neuronal diversity that is sufficient to establish functional neuronal circuits. However, the molecular mechanisms that specify the identity of each progenitor pool remain obscure. Here, we show that Wnt signaling is essential for the specification of the identity of posterior progenitor pools in the Drosophila visual center. In the medulla, the largest component of the visual center, different types of neurons are produced from two progenitor pools: the outer proliferation center (OPC) and glial precursor cells (GPCs; also known as tips of the OPC). We found that OPC-type neurons are produced from the GPCs at the expense of GPC-type neurons when Wnt signaling is suppressed in the GPCs. In contrast, GPC-type neurons are ectopically induced when Wnt signaling is ectopically activated in the OPC. These results suggest that Wnt signaling is necessary and sufficient for the specification of the progenitor pool identity. We also found that Homothorax (Hth), which is temporally expressed in the OPC, is ectopically induced in the GPCs by suppression of Wnt signaling and that ectopic induction of Hth phenocopies the suppression of Wnt signaling in the GPCs. Thus, Wnt signaling is involved in regionalization of the fly visual center through the specification of the progenitor pool located posterior to the medulla by suppressing Hth expression. SIGNIFICANCE STATEMENT: Brain consists of considerably diverse neurons of different origins. In mammalian brain, excitatory and inhibitory neurons derive from the dorsal and ventral telencephalon, respectively. Multiple progenitor pools also contribute to the neuronal diversity in fly brain. However, it has been unclear how differences between these progenitor pools are established. Here, we show that Wnt signaling, an evolutionarily conserved signaling, is involved in the process that establishes the differences between these progenitor pools. Because ß-catenin signaling, which is under the control of Wnt ligands, specifies progenitor pool identity in the developing mammalian thalamus, Wnt signaling-mediated specification of progenitor pool identity may be conserved in insect and mammalian brains.