Winged helix transcription factor BF-1 is essential for the development of the cerebral hemispheres

AbstractWe generated mice with a null mutation of the forebrain-restricted transcription factor BF-1 to examine its function in brain development. Heterozygous animals have an apparently normal phenotype. Homozygous null BF-1 mutants die at birth and have a dramatic reduction in the size of the cerebral hemispheres. The development of the ventral telencephalon is more severely affected than that of the dorsal telencephalon. Telencephalic neuroepithelial cells are specified in the BF-1 mutant, but their proliferation is reduced. Dorsal telencephalic neuroepithelial cells also differentiate prematurely, leading to early depletion of the progenitor population. These results suggest that BF-1 controls the morphogenesis of the telencephalon by regulating the rate of neuroepithelial cell proliferation and the timing of neuronal differentiation

Paleocortex is specified in mice in which dorsal telencephalic patterning is severely disrupted

The patterning of the telencephalon is regulated by the concerted action of distinct mechanisms operating in different portions of this structure. Although much progress has been made in understanding the mechanisms underlying the specification of dorsal and ventral structures, little is known about the specification of the paleocortex, the olfactory cortex located at the interface of the dorsal and ventral telencephalon. The paleocortex is thought to be a dorsal, cortical structure, derived from the lateral extreme of the dorsal telencephalon. We examined mutant mice in which dorsal telencephalic patterning is severely disrupted, to ask how these perturbations affect the paleocortex. In the Lhx2-/- telencephalon, where the cortex is greatly shrunken such that medial and dorsal cortical tissue is undetectable, normal expression of several paleocortical markers is observed. The Gli3-/- telencephalon, where the dorsal telencephalon is ventralized, also displays paleocortical markers. In contrast, when the ventral telencephalon is almost completely deleted, such as in the BF1-/- brain, paleocortical markers are undetectable. These results indicate that the specification of the paleocortex can occur in spite of drastic perturbations of dorsal patterning. Furthermore, in the Lhx2 mutant, the paleocortex is juxtaposed to an expanded and mislocated source of Wnt and Bmp signaling, the cortical hem, whereas, in the Gli3 mutant, paleocortical markers arise even though the cortical hem is missing. This indicates that an increase or decrease in cues from this dorsal signaling center does not disrupt the specification of the paleocortex. Finally, by using an in vitro assay, we found that isolated explants of lateral telencephalon up-regulate normal expression of paleocortical markers when maintained in vitro, from as early as embryonic day (E) 10.5. Together, the results reveal that, although the paleocortex is considered to be a cortical structure, it is specified even when dorsal telencephalic patterning is grossly perturbed. Furthermore, our in vitro data reveal that, if mechanisms outside the lateral telencephalon are involved in the specification of the paleocortex, they must act extremely early, prior to E10.5

Telencephalic progenitors maintain anteroposterior identities cell autonomously

Grafting experiments have demonstrated that determination of anteroposterior (AP) identity is an early step in neural patterning that precedes dorsoventral (DV) specification [1,2]. These studies used pieces of tissue, however, rather than individual cells to address this question. It thus remains unclear whether the maintenance of AP identity is a cell-autonomous property or a result of signaling between cells within the grafted tissue. Previously, we and others [3–5] have used transplants of dissociated brain cells to show that individual telencephalic precursor cells can adopt host-specific DV identities when they integrate within novel regions of the telencephalon. We have now undertaken a set of transplantations during the same mid-neurogenic period used in the previous studies to assess the ability of telencephalic progenitors to integrate and differentiate into more posterior regions of the neuraxis. We observed that telencephalic progenitors were capable of integrating and migrating within different AP levels of the central nervous system (CNS). Despite this, we found that telencephalic progenitors that integrated within the diencephalon and the mesencephalon continued to express a telencephalic marker until adulthood. We speculate that during neurogenesis individual progenitors are determined in terms of their AP but not their DV identity. Hence, AP identity is maintained cell autonomously within individual progenitors

An Epithelial Precursor Is Regulated by the Ureteric Bud and by the Renal Stroma

AbstractKidney epithelia develop from the metanephric mesenchyme after receiving inductive signals from the ureteric bud and from the renal stroma. However, it is not clear how these signals induce the different types of epithelia that make up the nephron. To investigate inductive signaling, we have isolated clusters of epithelial progenitors from the metanephric mesenchyme, thereby separating them from the renal stroma. When the isolated progenitors were treated with the ureteric bud factor LIF, they expressed epithelial proteins (ZO-1, E-cadherin, laminin α5) and produced nephrons (36 glomeruli with 58 tubules), indicating that they are the target of inductive signaling from the ureteric bud, and that renal stroma is not absolutely required for epithelial development in vitro. In fact, stroma-depleted epithelial progenitors produced sevenfold more glomeruli than did intact metanephric mesenchyme (5 glomeruli, 127 tubules). Conversely, when epithelial progenitors were treated with both LIF and proteins secreted from a renal stromal cell line, glomerulogenesis was abolished but tubular epithelia were expanded (0 glomeruli, 47 tubules). Hence, by isolating epithelial progenitors from the metanephric mesenchyme, we show that they are targeted by factors from the ureteric bud and from the renal stroma, and that epithelial diversification is stimulated by the ureteric bud and limited by renal stroma

Clinical studies of the DP1 antagonist laropiprant in asthma and allergic rhinitis

Background: Prostaglandin D-2 is a proinflammatory mediator believed to be important in asthma and allergic rhinitis (AR). Allelic variants in the prostaglandin D2 receptor type 1 (DP1) gene (PTGDR) have been suggested to be associated with asthma susceptibility. Objectives: We sought to investigate the efficacy of the DP1 antagonist laropiprant (alone or with montelukast) in asthma and seasonal AR and explore whether sequence variations in PTGDR are associated with asthma severity. Methods: For asthma, in a double-blind crossover study, 100 patients with persistent asthma were randomized to placebo or laropiprant, 300 mg/d for 3 weeks, followed by addition of montelukast, 10 mg/d for 2 weeks. PTGDR promoter haplotypes were categorized as high, medium, or low transcriptional efficiency. The primary efficacy end point was FEV1. For AR, in a double-blind parallel-group study, 767 patients sensitized to a regionally prevalent fall allergen with symptomatic fall rhinitis were allocated to laropiprant, 25 mg/d or 100 mg/d; cetirizine, 10mg/d; or placebo for 2 weeks. The primary end point was the Daytime Nasal Symptoms Score. Results: For asthma, no significant differences in FEV1 or asthma symptoms were noted for laropiprant versus placebo or laropiprant plus montelukast vs montelukast (differences between montelukast and placebo: P <= .001). No clear association was seen between haplotype pair (ie, diplotype) and asthma severity. For AR, although cetirizine (vs placebo) demonstrated an improvement in the Daytime Nasal Symptoms Score (P < .001), laropiprant did not. Conclusion: Laropiprant did not demonstrate efficacy in asthmatic patients or patients with AR. Variations in PTGDR did not appear related to baseline asthma severity or treatment response (NCT00533208; NCT00783601). (J Allergy Clin Immunol 2009;124:942-8.

A randomized, placebo-controlled clinical trial evaluating the safety and efficacy of the once-weekly DPP-4 inhibitor omarigliptin in patients with type 2 diabetes mellitus inadequately controlled by glimepiride and metformin

Abstract Background Type 2 diabetes (T2D) is a progressive disease that often requires a patient to use multiple antihyperglycemic agents to achieve glycemic control with disease progression. Omarigliptin is a once-weekly dipeptidyl peptidase-4 inhibitor. The purpose of this trial was to assess the efficacy and safety of adding omarigliptin to the treatment regimen of patients with T2D inadequately controlled by dual therapy with metformin and glimepiride. Methods Patients with T2D and HbA1c ≥7.5% and ≤10.5% while on metformin (≥1500 mg/day) and glimepiride (≥4 mg/day) were randomized to omarigliptin 25 mg once-weekly (N = 154) or placebo (N = 153) for 24 weeks. The primary objective was to assess whether omarigliptin was superior to placebo in reducing HbA1c at Week 24. Secondary objectives were to assess the effects of omarigliptin vs. placebo on FPG and the proportion of subjects attaining HbA1c goals of <7% and <6.5%. Results From a mean baseline HbA1c of 8.5% (omarigliptin) and 8.6% (placebo), the least squares (LS) mean change from baseline in HbA1c at Week 24 was −0.67% in the omarigliptin group and −0.06% in the placebo group, with a between-group difference (95% CI) of −0.61% (−0.85, −0.38). Treatment with omarigliptin resulted in a significantly greater reduction in FPG relative to placebo (LS mean difference [95% CI] -0.9 mmol/L [−1.4, −0.4]; p < 0.001). The proportion of patients achieving glycemic goals of <7.0% and <6.5% was higher in the omarigliptin group relative to the placebo group. The overall incidences of adverse events (AEs), serious AEs, drug-related AEs and discontinuations were generally similar between treatment groups. The incidence of symptomatic hypoglycemia was 10.5% in the omarigliptin group and 8.5% in the placebo group. Relative to baseline, omarigliptin and placebo treatments were associated with LS mean changes in body weight of −0.1 kg and −0.9 kg, respectively. Conclusion In patients with T2D and inadequate glycemic control on dual therapy with metformin and glimepiride, compared with placebo, once-weekly omarigliptin provided greater improvement in glycemic control and was generally well tolerated. Trial registration ClinicalTrials.gov: NCT01704261 , EudraCT Number: 2012-002612-10. Trial Registration Date: October 8, 2012