Colony context and size-dependent compensation mechanisms give rise to variations in nuclear growth trajectories.

To investigate the fundamental question of how cellular variations arise across spatiotemporal scales in a population of identical healthy cells, we focused on nuclear growth in hiPS cell colonies as a model system. We generated a 3D timelapse dataset of thousands of nuclei over multiple days, and developed open-source tools for image and data analysis and an interactive timelapse viewer for exploring quantitative features of nuclear size and shape. We performed a data-driven analysis of nuclear growth variations across timescales. We found that individual nuclear volume growth trajectories arise from short timescale variations attributable to their spatiotemporal context within the colony. We identified a strikingly time-invariant volume compensation relationship between nuclear growth duration and starting volume across the population. Notably, we discovered that inheritance plays a crucial role in determining these two key nuclear growth features while other growth features are determined by their spatiotemporal context and are not inherited.

Distinct Developmental Mechanisms Act Independently to Shape Biased Synaptic Divergence from an Inhibitory Neuron.

Neurons often contact more than one postsynaptic partner type and display stereotypic patterns of synaptic divergence. Such synaptic patterns usually involve some partners receiving more synapses than others. The developmental strategies generating "biased" synaptic distributions remain largely unknown. To gain insight, we took advantage of a compact circuit in the vertebrate retina, whereby the AII amacrine cell (AII AC) provides inhibition onto cone bipolar cell (BC) axons and retinal ganglion cell (RGC) dendrites, but makes the majority of its synapses with the BCs. Using light and electron microscopy, we reconstructed the morphology and connectivity of mouse retinal AII ACs across postnatal development. We found that AII ACs do not elaborate their presynaptic structures, the lobular appendages, until BCs differentiate about a week after RGCs are present. Lobular appendages are present in mutant mice lacking BCs, implying that although synchronized with BC axonal differentiation, presynaptic differentiation of the AII ACs is not dependent on cues from BCs. With maturation, AII ACs maintain a constant number of synapses with RGCs, preferentially increase synaptogenesis with BCs, and eliminate synapses with wide-field amacrine cells. Thus, AII ACs undergo partner type-specific changes in connectivity to attain their mature pattern of synaptic divergence. Moreover, AII ACs contact non-BCs to the same extent in bipolarless retinas, indicating that AII ACs establish partner-type-specific connectivity using diverse mechanisms that operate in parallel but independently.

Assembly and maintenance of GABAergic and Glycinergic circuits in the mammalian nervous system.

Inhibition in the central nervous systems (CNS) is mediated by two neurotransmitters: gamma-aminobutyric acid (GABA) and glycine. Inhibitory synapses are generally GABAergic or glycinergic, although there are synapses that co-release both neurotransmitter types. Compared to excitatory circuits, much less is known about the cellular and molecular mechanisms that regulate synaptic partner selection and wiring patterns of inhibitory circuits. Recent work, however, has begun to fill this gap in knowledge, providing deeper insight into whether GABAergic and glycinergic circuit assembly and maintenance rely on common or distinct mechanisms. Here we summarize and contrast the developmental mechanisms that regulate the selection of synaptic partners, and that promote the formation, refinement, maturation and maintenance of GABAergic and glycinergic synapses and their respective wiring patterns. We highlight how some parts of the CNS demonstrate developmental changes in the type of inhibitory transmitter or receptor composition at their inhibitory synapses. We also consider how perturbation of the development or maintenance of one type of inhibitory connection affects other inhibitory synapse types in the same circuit. Mechanistic insight into the development and maintenance of GABAergic and glycinergic inputs, and inputs that co-release both these neurotransmitters could help formulate comprehensive therapeutic strategies for treating disorders of synaptic inhibition.

Presynaptic partner selection during retinal circuit reassembly varies with timing of neuronal regeneration in vivo.

Whether neurons can restore their original connectivity patterns during circuit repair is unclear. Taking advantage of the regenerative capacity of zebrafish retina, we show here the remarkable specificity by which surviving neurons reassemble their connectivity upon regeneration of their major input. H3 horizontal cells (HCs) normally avoid red and green cones, and prefer ultraviolet over blue cones. Upon ablation of the major (ultraviolet) input, H3 HCs do not immediately increase connectivity with other cone types. Instead, H3 dendrites retract and re-extend to contact new ultraviolet cones. But, if regeneration is delayed or absent, blue-cone synaptogenesis increases and ectopic synapses are made with red and green cones. Thus, cues directing synapse specificity can be maintained following input loss, but only within a limited time period. Further, we postulate that signals from the major input that shape the H3 HC's wiring pattern during development persist to restrict miswiring after damage.