SummaryRadial glial progenitors (RGPs) are responsible for producing nearly all neocortical neurons. To gain insight into the patterns of RGP division and neuron production, we quantitatively analyzed excitatory neuron genesis in the mouse neocortex using Mosaic Analysis with Double Markers, which provides single-cell resolution of progenitor division patterns and potential in vivo. We found that RGPs progress through a coherent program in which their proliferative potential diminishes in a predictable manner. Upon entry into the neurogenic phase, individual RGPs produce ∼8–9 neurons distributed in both deep and superficial layers, indicating a unitary output in neuronal production. Removal of OTX1, a transcription factor transiently expressed in RGPs, results in both deep- and superficial-layer neuron loss and a reduction in neuronal unit size. Moreover, ∼1/6 of neurogenic RGPs proceed to produce glia. These results suggest that progenitor behavior and histogenesis in the mammalian neocortex conform to a remarkably orderly and deterministic program.

Radial glial cells are the primary neural progenitor cells in the developing neocortex 1. Consecutive asymmetric divisions of individual radial glial progenitor cells produce a number of sister excitatory neurons that migrate along the elongated radial glial fibre, resulting in the formation of ontogenetic columns 2–4. Moreover, sister excitatory neurons in ontogenetic columns preferentially develop specific chemical synapses with each other rather than with nearby non-siblings 5. While these findings provide crucial insights into the emergence of functional columns in the neocortex, little is known about the basis for this lineage-dependent assembly of excitatory neuron microcircuits with single-cell resolution. Here we show that transient electrical coupling between radially aligned sister excitatory neurons regulates the subsequent formation of specific chemical synapses in the neocortex. Multiple-electrode whole-cell recordings revealed that sister excitatory neurons preferentially form strong electrical coupling with each other rather than with adjacent non-sister excitatory neurons during early postnatal stages. This coupling allows selective electrical communication between sister excitatory neurons, promoting their action potential generation and synchronous firing. Interestingly, while this electrical communication largely disappears prior to the appearance of chemical synapses, its blockade impairs the subsequent formation of specific chemical synapses between sister excitatory neurons in ontogenetic columns. These results suggest a strong link between a lineage-dependent transient electrical coupling and the assembly of precise excitatory neuron microcircuits in the neocortex.

The neocortex contains excitatory neurons and inhibitory interneurons. Clones of neocortical excitatory neurons originating from the same progenitor cell are spatially organized and contribute to the formation of functional microcircuits. In contrast, relatively little is known about the production and organization of neocortical inhibitory interneurons. We found that neocortical inhibitory interneurons were produced as spatially organized clonal units in the developing ventral telencephalon. Furthermore, clonally related interneurons did not randomly disperse but formed spatially isolated clusters in the neocortex. Individual clonal clusters consisting of interneurons expressing the same or distinct neurochemical markers exhibited clear vertical or horizontal organization. These results suggest that the lineage relationship plays a pivotal role in the organization of inhibitory interneurons in the neocortex.

SUMMARYThe endocycle is a variant cell cycle consisting of successive DNA synthesis and Gap phases that yield highly polyploid cells. Although essential for metazoan development, relatively little is known about its control or physiologic role in mammals. Using novel lineage-specific cre mice we identified two opposing arms of the E2F program, one driven by canonical transcription activation (E2F1, E2F2 and E2F3) and the other by atypical repression (E2F7 and E2F8), that converge on the regulation of endocycles in vivo. Ablation of canonical activators in the two endocycling tissues of mammals, trophoblast giant cells in the placenta and hepatocytes in the liver, augmented genome ploidy, whereas ablation of atypical repressors diminished ploidy. These two antagonistic arms coordinate the expression of a unique G2/M transcriptional program that is critical for mitosis, karyokinesis and cytokinesis. These results provide in vivo evidence for a direct role of E2F family members in regulating non-traditional cell cycles in mammals.

<div><b>OBJECTIVE:</b> Diabetes is one of the most distinct comorbidities of COVID-19. Here, we described the clinical characteristics and outcomes in diabetic patients with confirmed or clinically diagnosed (with typical lung imaging features and symptoms) COVID-19, and their association with glucose lowering or blood pressure lowering medications.</div><div><br></div><div><b>RESEARCH DESIGN AND METHODS: </b>In this retrospective study involving 904 COVID-19 patients (136 with diabetes, mostly type 2 diabetes), clinical and laboratory characteristics were collected and compared between diabetic vs non-diabetic groups, and different medication groups. Logistic regression was used to explore risk factors associated with mortality or poor prognosis.</div><div><br></div><div><b>RESULTS:</b> Proportion of comorbid diabetes is similar between confirmed and clinically diagnosed COVID-19 cases. Risk factors for higher mortality of diabetic patients with COVID-19 were elder age (adjusted OR [aOR] 1.09 [95% CI 1.04, 1.15], per year increase, P = 0.001) and elevated C-reactive protein (aOR 1.12 [95% CI 1.00, 1.24], mg/dL, P = 0.043). Insulin usage (aOR 3.58 [95%CI 1.37, 9.35], P = 0.009) was associated with poor prognosis. Clinical outcomes of ACE inhibitor or angiotensin II type-I receptor blocker (ACEI/ARB) users were comparable to non-ACEI/ARB users in COVID-19 patients with diabetes and hypertension.</div><div><br></div><div><b>CONCLUSIONS: </b>C-reactive protein may help to identify diabetic patients with greater risk. Elder diabetic patients were prone to COVID-19-related fatality. Attentions need to be paid on insulin-using diabetic patients with COVID-19. ACEI/ARB showed no significant impact on COVID-19 patients with diabetes and hypertension.</div>