The P-body protein 4E-T represses translation to regulate the balance between cell genesis and establishment of the postnatal NSC pool.

Here, we ask how developing precursors maintain the balance between cell genesis for tissue growth and establishment of adult stem cell pools, focusing on postnatal forebrain neural precursor cells (NPCs). We show that these NPCs are transcriptionally primed to differentiate and that the primed mRNAs are associated with the translational repressor 4E-T. 4E-T also broadly associates with other NPC mRNAs encoding transcriptional regulators, and these are preferentially depleted from ribosomes, consistent with repression. By contrast, a second translational regulator, Cpeb4, associates with diverse target mRNAs that are largely ribosome associated. The 4E-T-dependent mRNA association is functionally important because 4E-T knockdown or conditional knockout derepresses proneurogenic mRNA translation and perturbs maintenance versus differentiation of early postnatal NPCs in culture and in vivo. Thus, early postnatal NPCs are primed to differentiate, and 4E-T regulates the balance between cell genesis and stem cell expansion by sequestering and repressing mRNAs encoding transcriptional regulators.

Quality Indicators for the Diagnosis and Management of Sudden Sensorineural Hearing Loss.

OBJECTIVE: Sudden sensorineural hearing loss (SSNHL) is an ideal entity for quality indicator (QI) development, providing treatment challenges resulting in variable or substandard care. The American Academy of Otolaryngology-Head and Neck Surgery recently updated their SSNHL guidelines. With SSNHL demonstrating a large burden of illness, this study sought to leverage the updated guidelines and develop QIs that support quality improvement initiatives at an individual, institutional, and systems level. METHODS: Candidate indicators (CIs) were extracted from high-quality SSNHL guidelines that were evaluated using the Appraisal of Guidelines for Research and Evaluation II tool. Each CI and its supporting evidence were summarized and reviewed by a nine-member expert panel based on validity, reliability, and feasibility of measurement. Final QIs were selected from CIs using the modified RAND Corporation-University of California, Los Angeles appropriateness methodology. RESULTS: Fifteen CIs were identified after literature review. After the first round of evaluations, the panel agreed on 11 candidate indicators as appropriate QIs with 2 additional CIs suggested for consideration. An expert panel meeting provided a platform to discuss areas of disagreement before final evaluations. The expert panel subsequently agreed upon 11 final QIs as appropriate measures of high-quality care for SSNHL. CONCLUSION: The 11 proposed QIs from this study are supported by evidence and expert consensus, facilitating measurement across a wide breadth of quality domains. With the recently updated SSNHL guidelines, and a greater focus on quality improvement opportunities, these QIs may be used by healthcare providers for targeted quality improvement initiatives.

Morbidity and mortality from adenotonsillectomy in children with trisomy 21.

OBJECTIVE: Adenotonsillectomy (AT) is common in children with trisomy 21 but outcomes are variable. Therefore, practitioners must have accurate information regarding the risks of the procedure specific to trisomy 21 to help patients weigh the risks and benefits of surgery. The objective of this study was to better characterize morbidity and mortality risk factors from AT in children with trisomy 21. METHODS: A single-center retrospective chart review of children with trisomy 21 who underwent AT was conducted from 1992 to 2019. The primary outcome was 30-day post-operative complication rate. Secondary outcomes included intraoperative complications, admission duration, emergency department visits, readmissions, reoperation rate and treatment failures. RESULTS: Two-hundred and fifty one children met study criteria (median age 4.5 years). Seventy-eight patients (31.5%) had a post-operative complication requiring medical intervention, with respiratory issues (42, 53.8%), poor oral intake (29, 37.2%), and bleeding (14, 17.9%) being most common. Postoperatively, 72 patients (28.7%) had a prolonged hospital stay. Sleep disordered breathing (p = 0.003), ASA score >2 (p < 0.001), severe OSA (p = 0.003), preoperative ICU admission (p < 0.001), and aerodigestive comorbidities (p = 0.004) were associated with increased post-operative respiratory complications. No mortalities were identified. CONCLUSION: This large single institution study evaluating morbidity and mortality following AT in children with trisomy 21 identified a morbidity rate of 31.5%. These findings may improve our ability to anticipate and manage postoperative morbidity in this vulnerable population and facilitate informed discussions with patients and caregivers considering AT.

Translating neural stem cells to neurons in the mammalian brain.

The mammalian neocortex underlies our perception of sensory information, performance of motor activities, and higher-order cognition. During mammalian embryogenesis, radial glial precursor cells sequentially give rise to diverse populations of excitatory cortical neurons, followed by astrocytes and oligodendrocytes. A subpopulation of these embryonic neural precursors persists into adulthood as neural stem cells, which give rise to inhibitory interneurons and glia. Although the intrinsic mechanisms instructing the genesis of these distinct progeny have been well-studied, most work to date has focused on transcriptional, epigenetic, and cell-cycle control. Recent studies, however, have shown that posttranscriptional mechanisms also regulate the cell fate choices of transcriptionally primed neural precursors during cortical development. These mechanisms are mediated primarily by RNA-binding proteins and microRNAs that coordinately regulate mRNA translation, stability, splicing, and localization. Together, these findings point to an extensive network of posttranscriptional control and provide insight into both normal cortical development and disease. They also add another layer of complexity to brain development and raise important biological questions for future investigation.

A Translational Repression Complex in Developing Mammalian Neural Stem Cells that Regulates Neuronal Specification.

The mechanisms instructing genesis of neuronal subtypes from mammalian neural precursors are not well understood. To address this issue, we have characterized the transcriptional landscape of radial glial precursors (RPs) in the embryonic murine cortex. We show that individual RPs express mRNA, but not protein, for transcriptional specifiers of both deep and superficial layer cortical neurons. Some of these mRNAs, including the superficial versus deep layer neuron transcriptional regulators Brn1 and Tle4, are translationally repressed by their association with the RNA-binding protein Pumilio2 (Pum2) and the 4E-T protein. Disruption of these repressive complexes in RPs mid-neurogenesis by knocking down 4E-T or Pum2 causes aberrant co-expression of deep layer neuron specification proteins in newborn superficial layer neurons. Thus, cortical RPs are transcriptionally primed to generate diverse types of neurons, and a Pum2/4E-T complex represses translation of some of these neuronal identity mRNAs to ensure appropriate temporal specification of daughter neurons.

Migrating Interneurons Secrete Fractalkine to Promote Oligodendrocyte Formation in the Developing Mammalian Brain.

During development, newborn interneurons migrate throughout the embryonic brain. Here, we provide evidence that these interneurons act in a paracrine fashion to regulate developmental oligodendrocyte formation. Specifically, we show that medial ganglionic eminence (MGE) interneurons secrete factors that promote genesis of oligodendrocytes from glially biased cortical precursors in culture. Moreover, when MGE interneurons are genetically ablated in vivo prior to their migration, this causes a deficit in cortical oligodendrogenesis. Modeling of the interneuron-precursor paracrine interaction using transcriptome data identifies the cytokine fractalkine as responsible for the pro-oligodendrocyte effect in culture. This paracrine interaction is important in vivo, since knockdown of the fractalkine receptor CX3CR1 in embryonic cortical precursors, or constitutive knockout of CX3CR1, causes decreased numbers of oligodendrocyte progenitor cells (OPCs) and oligodendrocytes in the postnatal cortex. Thus, in addition to their role in regulating neuronal excitability, interneurons act in a paracrine fashion to promote the developmental genesis of oligodendrocytes.

A Glo1-Methylglyoxal Pathway that Is Perturbed in Maternal Diabetes Regulates Embryonic and Adult Neural Stem Cell Pools in Murine Offspring.

Maternal diabetes is known to adversely influence brain development in offspring. Here, we provide evidence that this involves the circulating metabolite methylglyoxal, which is increased in diabetes, and its detoxifying enzyme, glyoxalase 1 (Glo1), which when mutated is associated with neurodevelopmental disorders. Specifically, when Glo1 levels were decreased in embryonic mouse cortical neural precursor cells (NPCs), this led to premature neurogenesis and NPC depletion embryonically and long-term alterations in cortical neurons postnatally. Increased circulating maternal methylglyoxal caused similar changes in embryonic cortical precursors and neurons and long-lasting changes in cortical neurons and NPCs in adult offspring. Depletion of embryonic and adult NPCs was also observed in murine offspring exposed to a maternal diabetic environment. Thus, the Glo1-methylglyoxal pathway integrates maternal and NPC metabolism to regulate neural development, and perturbations in this pathway lead to long-lasting alterations in adult neurons and NPC pools.

Proneurogenic Ligands Defined by Modeling Developing Cortex Growth Factor Communication Networks.

The neural stem cell decision to self-renew or differentiate is tightly regulated by its microenvironment. Here, we have asked about this microenvironment, focusing on growth factors in the embryonic cortex at a time when it is largely comprised of neural precursor cells (NPCs) and newborn neurons. We show that cortical NPCs secrete factors that promote their maintenance, while cortical neurons secrete factors that promote differentiation. To define factors important for these activities, we used transcriptome profiling to identify ligands produced by NPCs and neurons, cell-surface mass spectrometry to identify receptors on these cells, and computational modeling to integrate these data. The resultant model predicts a complex growth factor environment with multiple autocrine and paracrine interactions. We tested this communication model, focusing on neurogenesis, and identified IFNγ, Neurturin (Nrtn), and glial-derived neurotrophic factor (GDNF) as ligands with unexpected roles in promoting neurogenic differentiation of NPCs in vivo.