Phosphatidylinositol 3,4-bisphosphate regulates neurite initiation and dendrite morphogenesis via actin aggregation.

Neurite initiation is critical for neuronal morphogenesis and early neural circuit development. Recent studies showed that local actin aggregation underneath the cell membrane determined the site of neurite initiation. An immediately arising question is what signaling mechanism initiated actin aggregation. Here we demonstrate that local clustering of phosphatidylinositol 3,4-bisphosphate (PI(3,4)P2), a phospholipid with relatively few known signaling functions, is necessary and sufficient for aggregating actin and promoting neuritogenesis. In contrast, the related and more extensively studied phosphatidylinositol 4,5-bisphosphate or phosphatidylinositol (3,4,5)-trisphosphate (PIP3) molecules did not have such functions. Specifically, we showed that beads coated with PI(3,4)P2 promoted actin aggregation and neurite initiation, while pharmacological interference with PI(3,4)P2 synthesis inhibited both processes. PI(3,4)P2 clustering occurred even when actin aggregation was pharmacologically blocked, demonstrating that PI(3,4)P2 functioned as the upstream signaling molecule. Two enzymes critical for PI(3,4)P2 generation, namely, SH2 domain-containing inositol 5-phosphatase and class II phosphoinositide 3-kinase α, were complementarily and non-redundantly required for actin aggregation and neuritogenesis, as well as for subsequent dendritogenesis. Finally, we demonstrate that neural Wiskott-Aldrich syndrome protein and the Arp2/3 complex functioned downstream of PI(3,4)P2 to mediate neuritogenesis and dendritogenesis. Together, our results identify PI(3,4)P2 as an important signaling molecule during early development and demonstrate its critical role in regulating actin aggregation and neuritogenesis.

Actin Aggregations Mark the Sites of Neurite Initiation.

A salient feature of neurons is their intrinsic ability to grow and extend neurites, even in the absence of external cues. Compared to the later stages of neuronal development, such as neuronal polarization and dendrite morphogenesis, the early steps of neuritogenesis remain relatively unexplored. Here we showed that redistribution of cortical actin into large aggregates preceded neuritogenesis and determined the site of neurite initiation. Enhancing actin polymerization by jasplakinolide treatment effectively blocked actin redistribution and neurite initiation, while treatment with the actin depolymerizing agents latrunculin A or cytochalasin D accelerated neurite formation. Together, these results demonstrate a critical role of actin dynamics and reorganization in neurite initiation. Further experiments showed that microtubule dynamics and protein synthesis are not required for neurite initiation, but are required for later neurite stabilization. The redistribution of actin during early neuronal development was also observed in the cerebral cortex and hippocampus in vivo.

Severity assessment of intracranial large artery stenosis by pressure gradient measurements: A feasibility study.

BACKGROUND: Fractional flow reserve (FFR)-guided revascularization strategy is popular in coronary intervention. However, the feasibility of assessing stenotic severity in intracranial large arteries using pressure gradient measurements still remains unclear. METHODS: Between March 2013 and May 2014, 12 consecutive patients with intracranial large artery stenosis (including intracranial internal carotid artery, middle cerebral M1 segment, intracranial vertebral artery, and basilar artery) were enrolled in this study. The trans-stenotic pressure gradient was measured before and/or after percutaneous transluminal angioplasty and stenting (PTAS), and was then compared with percent diameter stenosis. A Pd /Pa cut-off of ≤0.70 was used to guide stenting of hemodynamically significant stenoses. The device-related and procedure-related serious adverse events and recurrent cerebral ischemic events were recorded. RESULTS: The target vessel could be reached in all cases. No technical complications occurred due to the specific study protocol. Excellent pressure signals were obtained in all patients. For seven patients who performed PTAS, the mean pre-procedural pressure gradient decreased from 59.0 ± 17.2 to 13.3 ± 13.6 mm Hg after the procedure (P < 0.01). Only one patient who refused stenting experienced a TIA event in the ipsilateral MCA territory. No recurrent ischemic event was observed in other patients. CONCLUSION: Mean trans-stenotic pressure gradients can be safely and easily measured with a 0.014-inch fluid-filled guide wire in intracranial large arteries. © 2016 Wiley Periodicals, Inc.

[Characteristics of erectile dysfunction in old males with lacunar infarction].

OBJECTIVE: To investigate the characteristics of erectile dysfunction (ED) in old males with lacunar infarction. METHODS: A total of 38 old patients ages from 60 to 70 years were involved. The questionnaire of international index of erectile function 5 (IIEF -5) was used to determine the status and severity of ED. According to the focus of infarction on MRI, the patients were divided into two groups, Group I with lacunar infarction and minor neurological deficits, and Group II with none. The total IIEF-5 scores were compared between the two groups and repeatedly evaluated six months after discharge. RESULTS: According to the total scores of IIEF-5, the prevalence of ED in Group II (95%) was higher, and the incidence of severe ED was significantly increased (60.0% vs. 44.4%, P < 0.05) as compared with Group II. In both the two groups, severe ED was more often seen in diabetic patients. At six months after discharge, the total scores of IIEF-5 were significantly increased (11.2 +/- 3.2 vs. 15.6 +/- 2.2, P < 0.05). CONCLUSION: ED is significantly increased in old males with lacunar infarction, and it is more severe in diabetic patients. Post-stroke rehabilitation care helps to improve ED.