Publications by authors named "Paul A Gray"

42 Publications

Zn-Templated synthesis of substituted (2,6-diimine)pyridine proligands and evaluation of their iron complexes as anolytes for flow battery applications.

Dalton Trans 2020 Nov;49(45):16175-16183

Department of Chemistry and the Manitoba Institute for Materials, University of Manitoba, 144 Dysart Road, Winnipeg, Manitoba R3T 2N2, Canada.

Pseudo-octahedral iron complexes supported by tridentate N^N^N-binding, redox 'non-innocent' diiminepyridine (DIP) ligands exhibit multiple reversible ligand-based reductions that suggest the potential application of these complexes as anolytes in redox flow batteries (RFBs). When bearing aryl groups at the imine nitrogens, substitution at the 4-position can be used to tune these redox potentials and impact other properties relevant to RFB applications, such as solubility and stability over extended cycling. DIP ligands bearing electron-withdrawing groups (EWGs) in this position, however, can be challenging to isolate via typical condensation routes involving para-substituted anilines and 2,6-diacetylpyridine. In this work, we demonstrate a high-yielding Zn-templated synthesis of DIP ligands bearing strong EWGs. The synthesis and electrochemical characterization of iron(ii) complexes of these ligands is also described, along with properties relevant to their potential application as RFB anolytes.
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http://dx.doi.org/10.1039/d0dt00543fDOI Listing
November 2020

Canada's uncharted conservation approach.

Science 2019 Jun;364(6447):1243

National Center for Scientific Research, PSL Université Paris, CRIOBE, USR 3278 CNRS-EPHE-UPVD, Maison des Océans, 75005 Paris, France.

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http://dx.doi.org/10.1126/science.aax9060DOI Listing
June 2019

Corrigendum to "Diving into the mammalian swamp of respiratory rhythm generation with the bullfrog" [Respir. Physiol. Neurobiol. 224 (2016) 37-51].

Respir Physiol Neurobiol 2018 09 9;255:58. Epub 2018 Feb 9.

Hotchkiss Brain Institute and Alberta Children's Hospital Research Institute, Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada. Electronic address:

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http://dx.doi.org/10.1016/j.resp.2018.01.012DOI Listing
September 2018

Tris(1-methyl-imidazol-2-yl)phosphane Complexes of Pnictogen, Tetrel, and Triel Cations.

Chemistry 2018 Mar 27;24(18):4718-4723. Epub 2018 Feb 27.

X-Ray Crystallography Laboratory, University of Alberta, Edmonton, Alberta, T6G 2T2, Canada.

cations gallium indium nitrogen ligands pnictogens tetrelThe synthesis and characterization of salts with the generic formula [P(Im) M][OTf] (Im=1-methyl-imidazol-2-yl; M=P, As or Sb and x=3; M=Ge or Sn and x=2) are reported. In all cases, the cations adopt a cage structure with two chemically and energetically distinct apical lone pairs. In contrast, complexes of gallium and indium engage two P(Im) ligands resulting in a distorted octahedral geometry for the triel center in compounds of the generic formula [{P(Im) } M][OTf] (M=Ga or In). An assessment of the acidity and basicity of the new compounds is presented.
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http://dx.doi.org/10.1002/chem.201706107DOI Listing
March 2018

Cationic 2,2'-bipyridine complexes of germanium(ii) and tin(ii).

Dalton Trans 2017 Jul;46(26):8363-8366

Department of Chemistry, University of Victoria, P.O Box 3065, Stn. CSC, Victoria, Canada.

We present the first systematic study of 2,2'-bipyridine complexes of E(ii) cationic acceptors (E = Ge, Sn). The complexes were comprehensively characterized by spectroscopic and crystallographic methods to yield complexes of ECl and E. Computational DFT methods were also employed to survey the bonding in the cations, along with an examination of their molecular orbitals (MOs).
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http://dx.doi.org/10.1039/c7dt02148hDOI Listing
July 2017

A subset of ipRGCs regulates both maturation of the circadian clock and segregation of retinogeniculate projections in mice.

Elife 2017 06 15;6. Epub 2017 Jun 15.

Department of Biology, Johns Hopkins University, Baltimore, United States.

The visual system consists of two major subsystems, image-forming circuits that drive conscious vision and non-image-forming circuits for behaviors such as circadian photoentrainment. While historically considered non-overlapping, recent evidence has uncovered crosstalk between these subsystems. Here, we investigated shared developmental mechanisms. We revealed an unprecedented role for light in the maturation of the circadian clock and discovered that intrinsically photosensitive retinal ganglion cells (ipRGCs) are critical for this refinement process. In addition, ipRGCs regulate retinal waves independent of light, and developmental ablation of a subset of ipRGCs disrupts eye-specific segregation of retinogeniculate projections. Specifically, a subset of ipRGCs, comprising ~200 cells and which project intraretinally and to circadian centers in the brain, are sufficient to mediate both of these developmental processes. Thus, this subset of ipRGCs constitute a shared node in the neural networks that mediate light-dependent maturation of the circadian clock and light-independent refinement of retinogeniculate projections.
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http://dx.doi.org/10.7554/eLife.22861DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5513697PMC
June 2017

Respiratory Network Stability and Modulatory Response to Substance P Require Nalcn.

Neuron 2017 Apr 6;94(2):294-303.e4. Epub 2017 Apr 6.

Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA; Howard Hughes Medical Institute, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address:

Respiration is a rhythmic activity as well as one that requires responsiveness to internal and external circumstances; both the rhythm and neuromodulatory responses of breathing are controlled by brainstem neurons in the preBötzinger complex (preBötC) and the retrotrapezoid nucleus (RTN), but the specific ion channels essential to these activities remain to be identified. Because deficiency of sodium leak channel, non-selective (Nalcn) causes lethal apnea in humans and mice, we investigated Nalcn function in these neuronal groups. We found that one-third of mice lacking Nalcn in excitatory preBötC neurons died soon after birth; surviving mice developed apneas in adulthood. Interestingly, in both preBötC and RTN neurons, the Nalcn current influences the resting membrane potential, contributes to maintenance of stable network activity, and mediates modulatory responses to the neuropeptide substance P. These findings reveal Nalcn's specific role in both rhythmic stability and responsiveness to neuropeptides within the respiratory network.
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http://dx.doi.org/10.1016/j.neuron.2017.03.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5702257PMC
April 2017

Barrington's nucleus: Neuroanatomic landscape of the mouse "pontine micturition center".

J Comp Neurol 2017 Jul 18;525(10):2287-2309. Epub 2017 Apr 18.

Department of Medicine & Neurology, Harvard Medical School, Boston, Massachusetts.

Barrington's nucleus (Bar) is thought to contain neurons that trigger voiding and thereby function as the "pontine micturition center." Lacking detailed information on this region in mice, we examined gene and protein markers to characterize Bar and the neurons surrounding it. Like rats and cats, mice have an ovoid core of medium-sized Bar neurons located medial to the locus coeruleus (LC). Bar neurons express a GFP reporter for Vglut2, develop from a Math1/Atoh1 lineage, and exhibit immunoreactivity for NeuN. Many neurons in and around this core cluster express a reporter for corticotrophin-releasing hormone (Bar ). Axons from Bar neurons project to the lumbosacral spinal cord and ramify extensively in two regions: the dorsal gray commissural and intermediolateral nuclei. Bar neurons have unexpectedly long dendrites, which may receive synaptic input from the cerebral cortex and other brain regions beyond the core afferents identified previously. Finally, at least five populations of neurons surround Bar: rostral-dorsomedial cholinergic neurons in the laterodorsal tegmental nucleus; lateral noradrenergic neurons in the LC; medial GABAergic neurons in the pontine central gray; ventromedial, small GABAergic neurons that express FoxP2; and dorsolateral glutamatergic neurons that express FoxP2 in the pLC and form a wedge dividing Bar from the dorsal LC. We discuss the implications of this new information for interpreting existing data and future experiments targeting Bar neurons and their synaptic afferents to study micturition and other pelvic functions.
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http://dx.doi.org/10.1002/cne.24215DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5832452PMC
July 2017

The neural control of respiration in lampreys.

Respir Physiol Neurobiol 2016 12 22;234:14-25. Epub 2016 Aug 22.

Groupe de Recherche sur le Système Nerveux Central (GRSNC), Département de neurosciences, Université de Montréal, Montréal, Québec, Canada; Groupe de Recherche en Activité Physique Adaptée (GRAPA), Département des sciences de l'activité physique, Université du Québec à Montréal, Montréal, Québec, Canada. Electronic address:

This review focuses on past and recent findings that have contributed to characterize the neural networks controlling respiration in the lamprey, a basal vertebrate. As in other vertebrates, respiration in lampreys is generated centrally in the brainstem. It is characterized by the presence of a fast and a slow respiratory rhythm. The anatomical and the basic physiological properties of the neural networks underlying the generation of the fast rhythm have been more thoroughly investigated; less is known about the generation of the slow respiratory rhythm. Comparative aspects with respiratory generators in other vertebrates as well as the mechanisms of modulation of respiration in association with locomotion are discussed.
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http://dx.doi.org/10.1016/j.resp.2016.08.007DOI Listing
December 2016

Dbx1 precursor cells are a source of inspiratory XII premotoneurons.

Elife 2015 Dec 19;4. Epub 2015 Dec 19.

Department of Physiology, Neuroscience and Mental Health Institute, Women and Children's Health Research Institute, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Canada.

All behaviors require coordinated activation of motoneurons from central command and premotor networks. The genetic identities of premotoneurons providing behaviorally relevant excitation to any pool of respiratory motoneurons remain unknown. Recently, we established in vitro that Dbx1-derived pre-Bötzinger complex neurons are critical for rhythm generation and that a subpopulation serves a premotor function (Wang et al., 2014). Here, we further show that a subpopulation of Dbx1-derived intermediate reticular (IRt) neurons are rhythmically active during inspiration and project to the hypoglossal (XII) nucleus that contains motoneurons important for maintaining airway patency. Laser ablation of Dbx1 IRt neurons, 57% of which are glutamatergic, decreased ipsilateral inspiratory motor output without affecting frequency. We conclude that a subset of Dbx1 IRt neurons is a source of premotor excitatory drive, contributing to the inspiratory behavior of XII motoneurons, as well as a key component of the airway control network whose dysfunction contributes to sleep apnea.
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http://dx.doi.org/10.7554/eLife.12301DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4764567PMC
December 2015

Absence of mutations in HCRT, HCRTR1 and HCRTR2 in patients with ROHHAD.

Respir Physiol Neurobiol 2016 Jan 10;221:59-63. Epub 2015 Nov 10.

Center for Autonomic Medicine in Pediatrics (CAMP) in Stanley Manne Children's Research Institute and in Department of Pediatrics, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, USA; Northwestern University Feinberg School of Medicine, Chicago, IL, USA. Electronic address:

Background And Objectives: Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD) is a rare pediatric disease of unknown cause. Here, in response to a recent case report describing a ROHHAD patient who suffered from secondary narcolepsy confirmed by an absence of hypocretin-1 in the cerebrospinal fluid, we consider whether the ROHHAD phenotype is owing to one or more mutations in genes specific to hypocretin protein signalling.

Methods: DNA samples from 16 ROHHAD patients were analyzed using a combination of next-generation and Sanger sequencing to identify exonic sequence variations in three genes: HCRT, HCRTR1, and HCRTR2.

Results: No rare or novel mutations were identified in the exons of HCRT, HCRTR1, or HCRTR2 genes in a set of 16 ROHHAD patients.

Conclusions: ROHHAD is highly unlikely to be caused by mutations in the exons of the genes for hypocretin and its two receptors.
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http://dx.doi.org/10.1016/j.resp.2015.11.002DOI Listing
January 2016

2-Phosphino-1,3-diphosphonium ions.

Dalton Trans 2016 Feb 22;45(5):2124-9. Epub 2015 Oct 22.

Department of Chemistry, University of Victoria, Victoria, British Columbia V8W 3V6, Canada.

A series of 2-phosphino-1,3-diphosphonium trifluoromethanesulfonate salts has been prepared and comprehensively characterized. The compounds represent rare examples of salts containing triphosphorus dications and establish important structural and spectroscopic parameters and trends for catenated phosphorus chains.
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http://dx.doi.org/10.1039/c5dt03116hDOI Listing
February 2016

Diving into the mammalian swamp of respiratory rhythm generation with the bullfrog.

Respir Physiol Neurobiol 2016 Apr 14;224:37-51. Epub 2015 Sep 14.

Hotchkiss Brain Institute and Alberta Children's Hospital Research Institute, Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada. Electronic address:

All vertebrates produce some form of respiratory rhythm, whether to pump water over gills or ventilate lungs. Yet despite the critical importance of ventilation for survival, the architecture of the respiratory central pattern generator has not been resolved. In frogs and mammals, there is increasing evidence for multiple burst-generating regions in the ventral respiratory group. These regions work together to produce the respiratory rhythm. However, each region appears to be pivotally important to a different phase of the motor act. Regions also exhibit differing rhythmogenic capabilities when isolated and have different CO2 sensitivity and pharmacological profiles. Interestingly, in both frogs and rats the regions with the most robust rhythmogenic capabilities when isolated are located in rhombomeres 7/8. In addition, rhombomeres 4/5 in both clades are critical for controlling phases of the motor pattern most strongly modulated by CO2 (expiration in mammals, and recruitment of lung bursts in frogs). These key signatures may indicate that these cell clusters arose in a common ancestor at least 400 million years ago.
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http://dx.doi.org/10.1016/j.resp.2015.09.005DOI Listing
April 2016

Rapid-Onset Obesity with Hypothalamic Dysfunction, Hypoventilation, and Autonomic Dysregulation (ROHHAD): exome sequencing of trios, monozygotic twins and tumours.

Orphanet J Rare Dis 2015 Aug 25;10:103. Epub 2015 Aug 25.

Department of Medical Genetics, Cumming School of Medicine, Alberta Children's Hospital Research Institute, University of Calgary, Calgary, AB, Canada.

Background: Rapid-onset Obesity with Hypothalamic Dysfunction, Hypoventilation, and Autonomic Dysregulation (ROHHAD) is thought to be a genetic disease caused by de novo mutations, though causative mutations have yet to be identified. We searched for de novo coding mutations among a carefully-diagnosed and clinically homogeneous cohort of 35 ROHHAD patients.

Methods: We sequenced the exomes of seven ROHHAD trios, plus tumours from four of these patients and the unaffected monozygotic (MZ) twin of one (discovery cohort), to identify constitutional and somatic de novo sequence variants. We further analyzed this exome data to search for candidate genes under autosomal dominant and recessive models, and to identify structural variations. Candidate genes were tested by exome or Sanger sequencing in a replication cohort of 28 ROHHAD singletons.

Results: The analysis of the trio-based exomes found 13 de novo variants. However, no two patients had de novo variants in the same gene, and additional patient exomes and mutation analysis in the replication cohort did not provide strong genetic evidence to implicate any of these sequence variants in ROHHAD. Somatic comparisons revealed no coding differences between any blood and tumour samples, or between the two discordant MZ twins. Neither autosomal dominant nor recessive analysis yielded candidate genes for ROHHAD, and we did not identify any potentially causative structural variations.

Conclusions: Clinical exome sequencing is highly unlikely to be a useful diagnostic test in patients with true ROHHAD. As ROHHAD has a high risk for fatality if not properly managed, it remains imperative to expand the search for non-exomic genetic risk factors, as well as to investigate other possible mechanisms of disease. In so doing, we will be able to confirm objectively the ROHHAD diagnosis and to contribute to our understanding of obesity, respiratory control, hypothalamic function, and autonomic regulation.
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http://dx.doi.org/10.1186/s13023-015-0314-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4548308PMC
August 2015

Testing the evolutionary conservation of vocal motoneurons in vertebrates.

Respir Physiol Neurobiol 2016 Apr 6;224:2-10. Epub 2015 Jul 6.

Department of Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address:

Medullary motoneurons drive vocalization in many vertebrate lineages including fish, amphibians, birds, and mammals. The developmental history of vocal motoneuron populations in each of these lineages remains largely unknown. The highly conserved transcription factor Paired-like Homeobox 2b (Phox2b) is presumed to be expressed in all vertebrate hindbrain branchial motoneurons, including laryngeal motoneurons essential for vocalization in humans. We used immunohistochemistry and in situ hybridization to examine Phox2b protein and mRNA expression in caudal hindbrain and rostral spinal cord motoneuron populations in seven species across five chordate classes. Phox2b was present in motoneurons dedicated to sound production in mice and frogs (bullfrog, African clawed frog), but not those in bird (zebra finch) or bony fish (midshipman, channel catfish). Overall, the pattern of caudal medullary motoneuron Phox2b expression was conserved across vertebrates and similar to expression in sea lamprey. These observations suggest that motoneurons dedicated to sound production in vertebrates are not derived from a single developmentally or evolutionarily conserved progenitor pool.
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http://dx.doi.org/10.1016/j.resp.2015.06.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4703570PMC
April 2016

Dysregulation of locus coeruleus development in congenital central hypoventilation syndrome.

Acta Neuropathol 2015 Aug 15;130(2):171-83. Epub 2015 May 15.

Department of Pediatrics, University of California San Francisco, 35 Medical Center Way, San Francisco, CA, 94143, USA.

Human congenital central hypoventilation syndrome (CCHS), resulting from mutations in transcription factor PHOX2B, manifests with impaired responses to hypoxemia and hypercapnia especially during sleep. To identify brainstem structures developmentally affected in CCHS, we analyzed two postmortem neonatal-lethal cases with confirmed polyalanine repeat expansion (PARM) or Non-PARM (PHOX2B∆8) mutation of PHOX2B. Both human cases showed neuronal losses within the locus coeruleus (LC), which is important for central noradrenergic signaling. Using a conditionally active transgenic mouse model of the PHOX2B∆8 mutation, we found that early embryonic expression (
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http://dx.doi.org/10.1007/s00401-015-1441-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4503865PMC
August 2015

Diverse reactivity of the cyclo-diphosphinophosphonium cation [(PtBu)₃Me]⁺: parallels with epoxides and new catena-phosphorus frameworks.

J Am Chem Soc 2014 Oct 13;136(42):14941-50. Epub 2014 Oct 13.

Department of Chemistry, University of Victoria , Victoria, British Columbia V8W 3V6, Canada.

The cyclo-diphosphinophosphonium salt [(PtBu)3Me][OTf] (2) has been shown to be highly reactive toward Lewis bases, exhibiting diverse reactivity with phosphines, 4-(dimethylamino)pyridine (dmap) and chlorophosphines, providing approaches to new open-chain and cyclic catena-phosphorus frameworks. Reaction of 2 with R3P (R = Me or nPr) or dmap led to the ring-opened adducts [R3P-PtBu-PtBu-P(Me)tBu][OTf] (R = Me (4a), nPr (4b)) and [(dmap)-PtBu-PtBu-P(Me)tBu][OTf] (6), respectively. The complicated (31)P{(1)H} NMR spectra of the three compounds were simulated, evidencing the presence of two diastereomeric forms of 4a, and single diastereomers of 4b and 6. This ring-opening reactivity of the cation in 2 parallels the reactivity of isolobal epoxides with nucleophiles under acidic conditions. Compound 2 was also shown to react with a 2:1 mixture of Me2PCl and TMSOTf to form the unexpected cyclo-diphosphino-1,2-diphosphonium salt [(Me2P)2(PtBu)2][OTf]2 (8), which is postulated to result from two consecutive ring-opening and ring-closing steps. In contrast, reaction with MePCl2 furnished [(MeP)(PtBu)2(P(Me)tBu)][OTf] (9), consistent with insertion of a "MeP" moiety into the cationic phosphorus framework of 2. The importance of ring strain on the reactivity of the cation in 2 was illustrated by comparative studies of the corresponding cyclo-tetraphosphorus cation in [(PtBu)4Me][OTf] (10), which exhibits no reactivity under analogous conditions.
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http://dx.doi.org/10.1021/ja507741sDOI Listing
October 2014

Testing the role of preBötzinger Complex somatostatin neurons in respiratory and vocal behaviors.

Eur J Neurosci 2014 Oct 21;40(7):3067-77. Epub 2014 Jul 21.

Department of Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, MO, 63110, USA.

Identifying neurons essential for the generation of breathing and related behaviors such as vocalisation is an important question for human health. The targeted loss of preBötzinger Complex (preBötC) glutamatergic neurons, including those that express high levels of somatostatin protein (SST neurons), eliminates normal breathing in adult rats. Whether preBötC SST neurons represent a functionally specialised population is unknown. We tested the effects on respiratory and vocal behaviors of eliminating SST neuron glutamate release by Cre-Lox-mediated genetic ablation of the vesicular glutamate transporter 2 (VGlut2). We found the targeted loss of VGlut2 in SST neurons had no effect on viability in vivo, or on respiratory period or responses to neurokinin 1 or μ-opioid receptor agonists in vitro. We then compared medullary SST peptide expression in mice with that of two species that share extreme respiratory environments but produce either high or low frequency vocalisations. In the Mexican free-tailed bat, SST peptide-expressing neurons extended beyond the preBötC to the caudal pole of the VII motor nucleus. In the naked mole-rat, however, SST-positive neurons were absent from the ventrolateral medulla. We then analysed isolation vocalisations from SST-Cre;VGlut2(F/F) mice and found a significant prolongation of the pauses between syllables during vocalisation but no change in vocalisation number. These data suggest that glutamate release from preBötC SST neurons is not essential for breathing but play a species- and behavior-dependent role in modulating respiratory networks. They further suggest that the neural network generating respiration is capable of extensive plasticity given sufficient time.
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http://dx.doi.org/10.1111/ejn.12669DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4383657PMC
October 2014

Interpnictogen cations: exploring new vistas in coordination chemistry.

Angew Chem Int Ed Engl 2014 Jun 26;53(24):6050-69. Epub 2014 May 26.

Department of Chemistry, University of Victoria, Victoria, BC V8W 3V6 (Canada).

Pnictine derivatives can behave as both 2e(-) donors (Lewis bases) and 2e(-) acceptors (Lewis acids). As prototypical ligands in the coordination chemistry of transition metals, amines and phosphines also form complexes with p-block Lewis acids, including a variety of pnictogen-centered acceptors. The inherent Lewis acidity of pnictogen centers can be enhanced by the introduction of a cationic charge, and this feature has been exploited in recent years in the development of compounds resulting from coordinate Pn-Pn and Pn-Pn' interactions. These compounds offer the unusual opportunity for homoatomic coordinate bonding and the development of complexes that possess a lone pair of electrons at the acceptor center. This Review presents new directions in the systematic extension of coordination chemistry from the transition series into the p-block.
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http://dx.doi.org/10.1002/anie.201307658DOI Listing
June 2014

Atoh1-dependent rhombic lip neurons are required for temporal delay between independent respiratory oscillators in embryonic mice.

Elife 2014 May 14;3:e02265. Epub 2014 May 14.

Department of Anatomy and Neurobiology, Washington University School of Medicine, St Louis, United States

All motor behaviors require precise temporal coordination of different muscle groups. Breathing, for example, involves the sequential activation of numerous muscles hypothesized to be driven by a primary respiratory oscillator, the preBötzinger Complex, and at least one other as-yet unidentified rhythmogenic population. We tested the roles of Atoh1-, Phox2b-, and Dbx1-derived neurons (three groups that have known roles in respiration) in the generation and coordination of respiratory output. We found that Dbx1-derived neurons are necessary for all respiratory behaviors, whereas independent but coupled respiratory rhythms persist from at least three different motor pools after eliminating or silencing Phox2b- or Atoh1-expressing hindbrain neurons. Without Atoh1 neurons, however, the motor pools become temporally disorganized and coupling between independent respiratory oscillators decreases. We propose Atoh1 neurons tune the sequential activation of independent oscillators essential for the fine control of different muscles during breathing.DOI: http://dx.doi.org/10.7554/eLife.02265.001.
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http://dx.doi.org/10.7554/eLife.02265DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4060005PMC
May 2014

ENaC-expressing neurons in the sensory circumventricular organs become c-Fos activated following systemic sodium changes.

Am J Physiol Regul Integr Comp Physiol 2013 Nov 18;305(10):R1141-52. Epub 2013 Sep 18.

Department of Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, Missouri.

The sensory circumventricular organs (CVOs) are specialized collections of neurons and glia that lie in the midline of the third and fourth ventricles of the brain, lack a blood-brain barrier, and function as chemosensors, sampling both the cerebrospinal fluid and plasma. These structures, which include the organum vasculosum of the lamina terminalis (OVLT), subfornical organ (SFO), and area postrema (AP), are sensitive to changes in sodium concentration but the cellular mechanisms involved remain unknown. Epithelial sodium channel (ENaC)-expressing neurons of the CVOs may be involved in this process. Here we demonstrate with immunohistochemical and in situ hybridization methods that ENaC-expressing neurons are densely concentrated in the sensory CVOs. These neurons become c-Fos activated, a marker for neuronal activity, after various manipulations of peripheral levels of sodium including systemic injections with hypertonic saline, dietary sodium deprivation, and sodium repletion after prolonged sodium deprivation. The increases seen c-Fos activity in the CVOs were correlated with parallel increases in plasma sodium levels. Since ENaCs play a central role in sodium reabsorption in kidney and other epithelia, we present a hypothesis here suggesting that these channels may also serve a related function in the CVOs. ENaCs could be a significant factor in modulating CVO neuronal activity by controlling the magnitude of sodium permeability in neurons. Hence, some of the same circulating hormones controlling ENaC expression in kidney, such as angiotensin II and atrial natriuretic peptide, may coordinate ENaC expression in sensory CVO neurons and could potentially orchestrate sodium appetite, osmoregulation, and vasomotor sympathetic drive.
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http://dx.doi.org/10.1152/ajpregu.00242.2013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4073964PMC
November 2013

Transcription factors define the neuroanatomical organization of the medullary reticular formation.

Authors:
Paul A Gray

Front Neuroanat 2013 14;7. Epub 2013 May 14.

Department of Anatomy and Neurobiology, Washington University School of Medicine St. Louis, MO, USA.

The medullary reticular formation contains large populations of inadequately described, excitatory interneurons that have been implicated in multiple homeostatic behaviors including breathing, viserosensory processing, vascular tone, and pain. Many hindbrain nuclei show a highly stereotyped pattern of localization across vertebrates suggesting a strong underlying genetic organization. Whether this is true for neurons within the reticular regions of hindbrain is unknown. Hindbrain neurons are derived from distinct developmental progenitor domains each of which expresses distinct patterns of transcription factors (TFs). These neuronal populations have distinct characteristics such as transmitter identity, migration, and connectivity suggesting developmentally expressed TFs might identify unique subpopulations of neurons within the reticular formation. A fate-mapping strategy using perinatal expression of reporter genes within Atoh1, Dbx1, Lmx1b, and Ptf1a transgenic mice coupled with immunohistochemistry (IHC) and in situ hybridization (ISH) were used to address the developmental organization of a large subset of reticular formation glutamatergic neurons. All hindbrain lineages have relatively large populations that extend the entire length of the hindbrain. Importantly, the location of neurons within each lineage was highly constrained. Lmx1b- and Dbx1- derived populations were both present in partially overlapping stripes within the reticular formation extending from dorsal to ventral brain. Within each lineage, distinct patterns of gene expression and organization were localized to specific hindbrain regions. Rostro-caudally sub-populations differ sequentially corresponding to proposed pseudo-rhombomereic boundaries. Dorsal-ventrally, sub-populations correspond to specific migratory positions. Together these data suggests the reticular formation is organized by a highly stereotyped developmental logic.
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http://dx.doi.org/10.3389/fnana.2013.00007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3653110PMC
June 2013

Translational profiling of hypocretin neurons identifies candidate molecules for sleep regulation.

Genes Dev 2013 Mar 21;27(5):565-78. Epub 2013 Feb 21.

Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, USA.

Hypocretin (orexin; Hcrt)-containing neurons of the hypothalamus are essential for the normal regulation of sleep and wake behaviors and have been implicated in feeding, anxiety, depression, and reward. The absence of these neurons causes narcolepsy in humans and model organisms. However, little is known about the molecular phenotype of these cells; previous attempts at comprehensive profiling had only limited sensitivity or were inaccurate. We generated a Hcrt translating ribosome affinity purification (bacTRAP) line for comprehensive translational profiling of all ribosome-bound transcripts in these neurons in vivo. From this profile, we identified >6000 transcripts detectably expressed above background and 188 transcripts that are highly enriched in these neurons, including all known markers of the cells. Blinded analysis of in situ hybridization databases suggests that ~60% of these are expressed in a Hcrt marker-like pattern. Fifteen of these were confirmed with double labeling and microscopy, including the transcription factor Lhx9. Ablation of this gene results in a >30% loss specifically of Hcrt neurons, without a general disruption of hypothalamic development. Polysomnography and activity monitoring revealed a profound hypersomnolence in these mice. These data provide an in-depth and accurate profile of Hcrt neuron gene expression and suggest that Lhx9 may be important for specification or survival of a subset of these cells.
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http://dx.doi.org/10.1101/gad.207654.112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3605469PMC
March 2013

Understanding the rhythm of breathing: so near, yet so far.

Annu Rev Physiol 2013 29;75:423-52. Epub 2012 Oct 29.

Department of Neurobiology, David Geffen School of Medicine, University of California, Los Angeles, California 90095-1763, USA.

Breathing is an essential behavior that presents a unique opportunity to understand how the nervous system functions normally, how it balances inherent robustness with a highly regulated lability, how it adapts to both rapidly and slowly changing conditions, and how particular dysfunctions result in disease. We focus on recent advancements related to two essential sites for respiratory rhythmogenesis: (a) the preBötzinger Complex (preBötC) as the site for the generation of inspiratory rhythm and (b) the retrotrapezoid nucleus/parafacial respiratory group (RTN/pFRG) as the site for the generation of active expiration.
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http://dx.doi.org/10.1146/annurev-physiol-040510-130049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3671763PMC
August 2013

Atoh1 governs the migration of postmitotic neurons that shape respiratory effectiveness at birth and chemoresponsiveness in adulthood.

Neuron 2012 Sep;75(5):799-809

Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA.

Hindbrain neuronal networks serving respiratory, proprioceptive, and arousal functions share a developmental requirement for the bHLH transcription factor Atoh1. Loss of Atoh1 in mice results in respiratory failure and neonatal lethality; however, the neuronal identity and mechanism by which Atoh1-dependent cells sustain newborn breathing remains unknown. We uncovered that selective loss of Atoh1 from the postmitotic retrotrapezoid nucleus (RTN) neurons results in severely impaired inspiratory rhythm and pronounced neonatal death. Mice that escape neonatal death develop abnormal chemoresponsiveness as adults. Interestingly, the expression of Atoh1 in the RTN neurons is not required for their specification or maintenance, but is important for their proper localization and to establish essential connections with the preBötzinger Complex (preBötC). These results provide insights into the genetic regulation of neonatal breathing and shed light on the labile sites that might contribute to sudden death in newborn infants and altered chemoresponsiveness in adults.
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http://dx.doi.org/10.1016/j.neuron.2012.06.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3464459PMC
September 2012

Genome-scale study of transcription factor expression in the branching mouse lung.

Dev Dyn 2012 Sep 20;241(9):1432-53. Epub 2012 Jul 20.

Laboratory of Genetics, University of Wisconsin-Madison, Madison, WI 53706, USA.

Background: Mammalian lung development consists of a series of precisely choreographed events that drive the progression from simple lung buds to the elaborately branched organ that fulfills the vital function of gas exchange. Strict transcriptional control is essential for lung development. Among the large number of transcription factors encoded in the mouse genome, only a small portion of them are known to be expressed and function in the developing lung. Thus a systematic investigation of transcription factors expressed in the lung is warranted.

Results: To enrich for genes that may be responsible for regional growth and patterning, we performed a screen using RNA in situ hybridization to identify genes that show restricted expression patterns in the embryonic lung. We focused on the pseudoglandular stage during which the lung undergoes branching morphogenesis, a cardinal event of lung development. Using a genome-scale probe set that represents over 90% of the transcription factors encoded in the mouse genome, we identified 62 transcription factor genes with localized expression in the epithelium, mesenchyme, or both. Many of these genes have not been previously implicated in lung development.

Conclusions: Our findings provide new starting points for the elucidation of the transcriptional circuitry that controls lung development.
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http://dx.doi.org/10.1002/dvdy.23823DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3529173PMC
September 2012

Identification of molecular compartments and genetic circuitry in the developing mammalian kidney.

Development 2012 May;139(10):1863-73

Department of Stem Cell and Regenerative Biology, Department of Molecular and Cellular Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA.

Lengthy developmental programs generate cell diversity within an organotypic framework, enabling the later physiological actions of each organ system. Cell identity, cell diversity and cell function are determined by cell type-specific transcriptional programs; consequently, transcriptional regulatory factors are useful markers of emerging cellular complexity, and their expression patterns provide insights into the regulatory mechanisms at play. We performed a comprehensive genome-scale in situ expression screen of 921 transcriptional regulators in the developing mammalian urogenital system. Focusing on the kidney, analysis of regional-specific expression patterns identified novel markers and cell types associated with development and patterning of the urinary system. Furthermore, promoter analysis of synexpressed genes predicts transcriptional control mechanisms that regulate cell differentiation. The annotated informational resource (www.gudmap.org) will facilitate functional analysis of the mammalian kidney and provides useful information for the generation of novel genetic tools to manipulate emerging cell populations.
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http://dx.doi.org/10.1242/dev.074005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3328182PMC
May 2012

Development, maturation, and necessity of transcription factors in the mouse suprachiasmatic nucleus.

J Neurosci 2011 Apr;31(17):6457-67

Department of Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.

The suprachiasmatic nucleus (SCN) of the hypothalamus is the master mammalian circadian clock. The SCN is highly specialized because it is responsible for generating a near 24 h rhythm, integrating external cues, and translating the rhythm throughout the body. Currently, our understanding of the developmental origin and genetic program involved in the proper specification and maturation of the SCN is limited. Herein, we provide a detailed analysis of transcription factor (TF) and developmental-gene expression in the SCN from neurogenesis to adulthood in mice (Mus musculus). TF expression within the postmitotic SCN was not static but rather showed specific temporal and spatial changes during prenatal and postnatal development. In addition, we found both global and regional patterns of TF expression extending into the adult. We found that the SCN is derived from a distinct region of the neuroepithelium expressing a combination of developmental genes: Six3, Six6, Fzd5, and transient Rx, allowing us to pinpoint the origin of this region within the broader developing telencephalon/diencephalon. We tested the necessity of two TFs in SCN development, RORα and Six3, which were expressed during SCN development, persisted into adulthood, and showed diurnal rhythmicity. Loss of RORα function had no effect on SCN peptide expression or localization. In marked contrast, the conditional deletion of Six3 from early neural progenitors completely eliminated the formation of the SCN. Our results provide the first description of the involvement of TFs in the specification and maturation of a neural population necessary for circadian behavior.
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http://dx.doi.org/10.1523/JNEUROSCI.5385-10.2011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3106226PMC
April 2011

FoxP2 expression defines dorsolateral pontine neurons activated by sodium deprivation.

Brain Res 2011 Feb 23;1375:19-27. Epub 2010 Nov 23.

Two specific groups of neurons in the dorsolateral pons are activated by dietary sodium deprivation. These two groups are the pre-locus coeruleus (pre-LC) and the inner subdivision of the external lateral parabrachial nucleus (PBel-inner). In each site, after rats are fed an extremely low-sodium diet for over a week, neurons increase their expression of an activity-induced transcription factor, c-Fos. Here, we confirm this observation and extend it by demonstrating that these two groups of neurons express a common marker gene, the constitutively-expressed transcription factor Forkhead box protein 2 (FoxP2). That is, virtually all of the c-Fos activated neurons in both regions also express FoxP2. The expression of FoxP2 by both these groups of neurons suggests that they are developmentally-related subsets derived from the same basic population. Given that FoxP2, unlike c-Fos, is expressed independent of sodium deprivation, this marker may be useful in future studies of the pre-LC and PBel-inner. The molecular definition of these neurons, which project to circuits in the forebrain that influence visceral, appetitive, and hedonic functions, may allow direct experimental exploration of the functional role of these circuits using genetic tools.
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http://dx.doi.org/10.1016/j.brainres.2010.11.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3034829PMC
February 2011

Developmental origin of preBötzinger complex respiratory neurons.

J Neurosci 2010 Nov;30(44):14883-95

Department of Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.

A subset of preBötzinger Complex (preBötC) neurokinin 1 receptor (NK1R) and somatostatin peptide (SST)-expressing neurons are necessary for breathing in adult rats, in vivo. Their developmental origins and relationship to other preBötC glutamatergic neurons are unknown. Here we show, in mice, that the "core" of preBötC SST(+)/NK1R(+)/SST 2a receptor(+) (SST2aR) neurons, are derived from Dbx1-expressing progenitors. We also show that Dbx1-derived neurons heterogeneously coexpress NK1R and SST2aR within and beyond the borders of preBötC. More striking, we find that nearly all non-catecholaminergic glutamatergic neurons of the ventrolateral medulla (VLM) are also Dbx1 derived. PreBötC SST(+) neurons are born between E9.5 and E11.5 in the same proportion as non-SST-expressing neurons. Additionally, preBötC Dbx1 neurons are respiratory modulated and show an early inspiratory phase of firing in rhythmically active slice preparations. Loss of Dbx1 eliminates all glutamatergic neurons from the respiratory VLM including preBötC NK1R(+)/SST(+) neurons. Dbx1 mutant mice do not express any spontaneous respiratory behaviors in vivo. Moreover, they do not generate rhythmic inspiratory activity in isolated en bloc preparations even after acidic or serotonergic stimulation. These data indicate that preBötC core neurons represent a subset of a larger, more heterogeneous population of VLM Dbx1-derived neurons. These data indicate that Dbx1-derived neurons are essential for the expression and, we hypothesize, are responsible for the generation of respiratory behavior both in vitro and in vivo.
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http://dx.doi.org/10.1523/JNEUROSCI.4031-10.2010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3056489PMC
November 2010