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1.  Synaptic Localization of α5 GABA (A) Receptors via Gephyrin Interaction Regulates Dendritic Outgrowth and Spine Maturation 
Developmental neurobiology  2015;75(11):1241-1251.
GABAA receptor subunit composition is a critical determinant of receptor localization and physiology, with synaptic receptors generating phasic inhibition and extrasynaptic receptors producing tonic inhibition. Extrasynaptically localized α5 GABAA receptors are largely responsible for tonic inhibition in hippocampal neurons. However, we show here that inhibitory synapses also contain a constant level of α5 GABAA receptors throughout neuronal development, as measured by its colocalization with gephyrin, the inhibitory postsynaptic scaffolding protein. Immunoprecipitation of the α5 subunit from both cultured neurons and adult rat brain coimmunoprecipitated gephyrin, confirming this interaction in vivo. Furthermore, the α5 subunit can interact with gephyrin independent of other synaptically localized alpha subunits, as shown by immunoprecipitation experiments in HEK cells. By replacing the α5 predicted gephyrin binding domain (Residues 370–385) with either the high affinity gephyrin binding domain of the α2 subunit or homologous residues from the extrasynaptic α4 subunit that does not interact with gephyrin, α5 GABAA receptor localization shifted into or out of the synapse, respectively. These shifts in the ratio of synaptic/extrasynaptic α5 localization disrupted dendritic outgrowth and spine maturation. In contrast to the predominant view of α5 GABAA receptors being extrasynaptic and modulating tonic inhibition, we identify an intimate association of the α5 subunit with gephyrin, resulting in constant synaptic levels of α5 GABAAR throughout circuit formation that regulates neu ronal development.
doi:10.1002/dneu.22280
PMCID: PMC5240477  PMID: 25663431
alpha 5 GABA(A)R; gephyrin; spine morphology; dendritic outgrowth
2.  Lesions targeted to the anterior forebrain disrupt vocal variability associated with testosterone-induced sensorimotor song development in adult female canaries, Serinus canaria 
Developmental neurobiology  2015;76(1):3-18.
Learned communication is a trait observed in a limited number of vertebrates such as humans but also songbirds (i.e. species in the suborder passeri sometimes called oscines). Robust male-biased sex-differences in song development and production have been observed in several songbird species. However, in some of these species treating adult females with testosterone (T) induces neuro-behavioral changes such that females become more male-like in brain and behavior. T-treatment in these adult females seems to stimulate sensorimotor song development to facilitate song masculinization. In male songbirds it is known that the lateral magnocellular nucleus of the anterior nidopallium (LMAN) plays a modulatory role during song development. LMAN is androgen sensitive and may be a key target of a T-induced recapitulation of a developmental process in adult females. We tested this hypothesis. Adult female canaries were given either a chemical lesion of LMAN or a control sham-surgery. Prior to surgery birds were individually housed for two-weeks in sound-attenuated chambers to record baseline vocal behavior. Post-surgery birds were given one-week to recover before subcutaneous implantation with silastic capsules filled with crystalline-T. Birds remained on treatment for three-weeks (behavioral recordings continued throughout). Birds with a lesion to LMAN had less variability in their song compared to controls. The diversity of syllable and phrase type(s) was greater in sham controls as compared to birds with LMAN lesions. Birds did not differ in song rate. These data suggest that the sustention and conclusion of T-induced sensorimotor song development in adult female canaries requires an intact LMAN.
doi:10.1002/dneu.22295
PMCID: PMC4600635  PMID: 25864444
3.  Zebrafish cerebrospinal fluid mediates cell survival through a retinoid signaling pathway 
Developmental neurobiology  2015;76(1):75-92.
Cerebrospinal fluid (CSF) includes conserved factors whose function is largely unexplored. To assess the role of CSF during embryonic development, CSF was repeatedly drained from embryonic zebrafish brain ventricles soon after their inflation. Removal of CSF increased cell death in the diencephalon, indicating a survival function. Factors within the CSF are required for neuroepithelial cell survival as injected mouse CSF but not artificial CSF could prevent cell death after CSF depletion. Mass spectrometry analysis of the CSF identified retinol binding protein 4 (Rbp4), which transports retinol, the precursor to retinoic acid (RA). Consistent with a role for Rbp4 in cell survival, inhibition of Rbp4 or RA synthesis increased neuroepithelial cell death. Conversely, ventricle injection of exogenous human RBP4 plus retinol, or RA alone prevented cell death after CSF depletion. Zebrafish rbp4 is highly expressed in the yolk syncytial layer, suggesting Rbp4 protein and retinol/RA precursors can be transported into the CSF from the yolk. In accord with this suggestion, injection of human RBP4 protein into the yolk prevents neuroepithelial cell death in rbp4 loss-of-function embryos. Together, these data support the model that Rbp4 and RA precursors are present within the CSF and used for synthesis of RA, which promotes embryonic neuroepithelial survival.
doi:10.1002/dneu.22300
PMCID: PMC4644717  PMID: 25980532
cerebrospinal fluid; retinoic acid; cell survival; brain development; RBP4
4.  The Drosophila ortholog of the ZC3H14 RNA binding protein acts within neurons to pattern axon projection in the developing brain 
Developmental neurobiology  2015;76(1):93-106.
The dNab2 polyadenosine RNA binding protein is the D. melanogaster ortholog of the vertebrate ZC3H14 protein, which is lost in a form of inherited intellectual disability (ID). Human ZC3H14 can rescue D. melanogaster dNab2 mutant phenotypes when expressed in all neurons of the developing nervous system, suggesting that dNab2/ZC3H14 performs well-conserved roles in neurons. However, the cellular and molecular requirements for dNab2/ZC3H14 in the developing nervous system have not been defined in any organism. Here we show that dNab2 is autonomously required within neurons to pattern axon projection from Kenyon neurons into the mushroom bodies, which are required for associative olfactory learning and memory in insects. Mushroom body axons lacking dNab2 project aberrantly across the brain midline and also show evidence of defective branching. Coupled with the prior finding that ZC3H14 is highly expressed in rodent hippocampal neurons, this requirement for dNab2 in mushroom body neurons suggests that dNab2/ZC3H14 has a conserved role in supporting axon projection and branching. Consistent with this idea, loss of dNab2 impairs short-term memory in a courtship conditioning assay. Taken together these results reveal a cell-autonomous requirement for the dNab2 RNA binding protein in mushroom body development and provide a window into potential neurodevelopmental functions of the human ZC3H14 protein.
doi:10.1002/dneu.22301
PMCID: PMC4644733  PMID: 25980665
5.  MicroRNAs in the axon locally mediate the effects of chondroitin sulfate proteoglycans and cGMP on axonal growth 
Developmental neurobiology  2015;75(12):1402-1419.
Axonal miRNAs locally regulate axonal growth by modulating local protein composition. Whether localized miRNAs in the axon mediate the inhibitory effect of CSPGs on the axon remains unknown. We showed that in cultured cortical neurons, axonal application of CSPGs inhibited axonal growth and altered axonal miRNA profiles, whereas elevation of axonal cGMP levels by axonal application of sildenafil reversed the effect of CSPGs on inhibition of axonal growth and on miRNA profiles. Specifically, CSPGs elevated and reduced axonal levels of miR-29c and ITGB1 proteins, respectively, while elevation of cGMP levels overcame these CSPG effects. Gain-of- and loss-of-function experiments demonstrated that miR-29c in the distal axon mediates axonal growth downstream of CSPGs and cGMP by regulating axonal protein levels of ITGB1, FAK, and RhoA. Together, our data demonstrate that axonal miRNAs play an import role in mediating the inhibitory action of CSPGs on axonal growth and that miR-29c at least partially mediates this process.
doi:10.1002/dneu.22292
PMCID: PMC4575244  PMID: 25788427
6.  Dynamic gene expression in the song system of zebra finches during the song learning period 
Developmental neurobiology  2015;75(12):1315-1338.
The brain circuitry that controls song learning and production undergoes marked changes in morphology and connectivity during the song learning period in juvenile zebra finches, in parallel to the acquisition, practice and refinement of song. Yet, the genetic programs and timing of regulatory change that establish the neuronal connectivity and plasticity during this critical learning period remain largely undetermined. To address this question, we used in situ hybridization (ISH) to compare the expression patterns of a set of thirty known robust molecular markers of HVC and/or area X, major telencephalic song nuclei, between adult and juvenile male zebra finches at different ages during development (20, 35, 50 days post-hatch, dph). We found that several of the genes examined undergo substantial changes in expression within HVC or its surrounds, and/or in other song nuclei. They fit into broad patterns of regulation, including those whose expression within HVC during this period increases (COL12A1, COL 21A1, MPZL1, PVALB, and CXCR7) or decreases (e.g. KCNT2, SAP30L), as well as some that show decreased expression in the surrounding tissue with little change within song nuclei (e.g. SV2B, TAC1). These results reveal a broad range of molecular changes that occur in the song system in concert with the song learning period. Some of the genes and pathways identified are potential modulators of the developmental changes associated with the emergence of the adult properties of the song control system, and/or the acquisition of learned vocalizations in songbirds.
doi:10.1002/dneu.22286
PMCID: PMC4575259  PMID: 25787707
Zebra finch; Brain development; Gene expression; Song system; Vocal learning
7.  Nerve Growth Factor Promotes Reorganization of the Axonal Microtubule Array at Sites of Axon Collateral Branching 
Developmental neurobiology  2015;75(12):1441-1461.
The localized debundling of the axonal microtubule array and the entry of microtubules into axonal filopodia are two defining features of collateral branching. We report that nerve growth factor (NGF), a branch inducing signal, increases the frequency of microtubule debundling along the axon shaft of chicken embryonic sensory neurons. Sites of debundling correlate strongly with the localized targeting of microtubules into filopodia. Platinum replica electron microscopy suggests physical interactions between debundled microtubules and axonal actin filaments. However, as evidenced by depolymerization of actin filaments and inhibition of myosin II, actomyosin force generation does not promote debundling. In contrast, loss of actin filaments or inhibition of myosin II activity promotes debundling, indicating that axonal actomyosin forces suppress debundling. MAP1B is a microtubule associated protein that represses axon branching. Following treatment with NGF, microtubules penetrating filopodia during the early stages of branching exhibited lower levels of associated MAP1B. NGF increased and decreased the levels of MAP1B phosphorylated at a GSK-3β site (pMAP1B) along the axon shaft and within axonal filopodia, respectively. The levels of MAP1B and pMAP1B were not altered at sites of debundling, relative to the rest of the axon. Unlike the previously determined effects of NGF on the axonal actin cytoskeleton, the effects of NGF on microtubule debundling were not affected by inhibition of protein synthesis. Collectively, these data indicate that NGF promotes localized axonal microtubule debundling, that actomyosin forces antagonize microtubule debundling and that NGF regulates pMAP1B in axonal filopodia during the early stages of collateral branch formation.
doi:10.1002/dneu.22294
PMCID: PMC4827620  PMID: 25846486
splaying; debundling; bundling; transport; microtubule associated protein 1B; contractility; myosin II; sprout; sprouting; consolidation; GSK3-β
8.  Ear Manipulations Reveal a Critical Period for Survival and Dendritic Development at the Single-Cell Level in Mauthner Neurons 
Developmental neurobiology  2015;75(12):1339-1351.
Second-order sensory neurons are dependent on afferents from the sense organs during a critical period in development for their survival and differentiation. Past research has mostly focused on whole populations of neurons, hampering progress in understanding the mechanisms underlying these critical phases. To move toward a better understanding of the molecular and cellular basis of afferent-dependent neuronal development, we developed a new model to study the effects of ear removal on a single identifiable cell in the hindbrain of a frog, the Mauthner cell. Ear extirpation at various stages of Xenopus laevis development defines a critical period of progressively-reduced dependency of Mauthner cell survival/differentiation on the ear afferents. Furthermore, ear removal results in a progressively decreased reduction in the number of dendritic branches. Conversely, addition of an ear results in an increase in the number of dendritic branches. These results suggest that the duration of innervation and the number of inner ear afferents play a quantitative role in Mauthner cell survival/differentiation, including dendritic development.
doi:10.1002/dneu.22287
PMCID: PMC5010663  PMID: 25787878
mauthner cell; cell survival; dendritic branching; Xenopus laevis
9.  mTOR kinase is needed for the development and stabilization of dendritic arbors in newly born olfactory bulb neurons 
Developmental Neurobiology  2016;76(12):1308-1327.
ABSTRACT
Neurogenesis is the process of neuron generation, which occurs not only during embryonic development but also in restricted niches postnatally. One such region is called the subventricular zone (SVZ), which gives rise to new neurons in the olfactory bulb (OB). Neurons that are born postnatally migrate through more complex territories and integrate into fully functional circuits. Therefore, differences in the differentiation of embryonic and postnatally born neurons may exist. Dendritogenesis is an important process for the proper formation of future neuronal circuits. Dendritogenesis in embryonic neurons cultured in vitro was shown to depend on the mammalian target of rapamycin (mTOR). Still unknown, however, is whether mTOR could regulate the dendritic arbor morphology of SVZ‐derived postnatal OB neurons under physiological conditions in vivo. The present study used in vitro cultured and differentiated SVZ‐derived neural progenitors and found that both mTOR complex 1 and mTOR complex 2 were required for the dendritogenesis of SVZ‐derived neurons. Furthermore, using a combination of in vivo electroporation of neural stem cells in the SVZ and genetic and pharmacological inhibition of mTOR, it was found that mTOR was crucial for the growth of basal and apical dendrites in postnatally born OB neurons under physiological conditions and contributed to the stabilization of their basal dendrites. © 2016 Wiley Periodicals, Inc. Develop Neurobiol 76: 1308–1327, 2016
doi:10.1002/dneu.22392
PMCID: PMC5132010  PMID: 27008592
postnatal neurogenesis; mTOR; dendritogenesis; olfactory bulb; in vivo electroporation
10.  REM Sleep Twitches Rouse Nascent Cerebellar Circuits: Implications for Sensorimotor Development 
Developmental neurobiology  2014;75(10):1140-1153.
The cerebellum is critical for sensorimotor integration and undergoes extensive postnatal development. During the first postnatal week in rats, climbing fibers polyinnervate Purkinje cells and, before granule cell migration, mossy fibers make transient, direct connections with Purkinje cells. Activity-dependent processes are assumed to play a critical role in the development and refinement of these and other aspects of cerebellar circuitry. However, the sources and patterning of activity have not been described. We hypothesize that sensory feedback (i.e., reafference) from myoclonic twitches in sleeping newborn rats is a prominent driver of activity for the developing cerebellum. Here, in 6-day-old rats, we show that Purkinje cells exhibit substantial state-dependent changes in complex and simple spike activity—primarily during active sleep. In addition, this activity increases significantly during bouts of twitching. Moreover, the surprising observation of twitch-dependent increases in simple spike activity at this age suggests a functional engagement of mossy fibers before the parallel fiber system has developed. Based on these and other results, we propose that twitching comprises a unique class of self-produced movement that drives critical aspects of activity-dependent development in the cerebellum and other sensorimotor systems.
doi:10.1002/dneu.22177
PMCID: PMC4177987  PMID: 24677804
cerebellum; myoclonic twitching; sleep; reafference; corollary discharge
11.  Looking to the eyes influences the processing of emotion on face-sensitive event-related potentials in 7-month-old infants 
Developmental neurobiology  2014;75(10):1154-1163.
Previous studies in infants have shown that face-sensitive components of the ongoing EEG (the event-related potential, or ERP) are larger in amplitude to negative emotions (e.g., fear, anger) versus positive emotions (e.g., happy). However, it is still unclear whether the negative emotions linked with the face or the negative emotions alone contribute to these amplitude differences. We simultaneously recorded infant looking behaviors (via eye-tracking) and face-sensitive ERPs while 7-month-old infants viewed human faces or animals displaying happy, fear, or angry expressions. We observed that the amplitude of the N290 was greater (i.e., more negative) to angry animals compared to happy or fearful animals; no such differences were obtained for human faces. Eye-tracking data highlighted the importance of the eye region in processing emotional human faces. Infants that spent more time looking to the eye region of human faces showing fearful or angry expressions had greater N290 or P400 amplitudes, respectively.
doi:10.1002/dneu.22204
PMCID: PMC4284144  PMID: 24962465
face processing; infant development; event-related potentials; eye tracking; emotions
12.  Neonatal over-expression of estrogen receptor-α alters midbrain dopamine neuron development and reverses the effects of low maternal care in female offspring 
Developmental neurobiology  2014;75(10):1114-1124.
Maternal behavior is dependent on estrogen receptor-alpha (ERα; Esr1) and oxytocin receptor (OTR) signaling in the medial preoptic area (MPOA) of the hypothalamus, as well as dopamine signaling from the ventral tegmental area (VTA) to forebrain regions. Previous studies in rats indicate that low levels of maternal care, particularly licking/grooming (LG), lead to reduced levels of MPOA ERα and VTA dopamine neurons in female offspring and predict lower levels of postpartum maternal behavior by these offspring. The aim of the current study was to determine the functional impact on maternal behavior of neonatal manipulation of ERα in females that had experienced low vs. high levels of postnatal maternal LG. Adenovirus expressing ESR1 was targeted to the MPOA in female pups from low and high LG litters on postnatal day 2–3. Over-expression of ESR1 in low LG offspring elevated the level of ERα-immunoreactive cells in the MPOA and of tyrosine hydroxylase cells in the VTA to that observed in high LG females. Amongst juvenile female low LG offspring, ESR1 over-expression also decreased the latency to engage in maternal behavior toward donor pups. These results show that virally-mediated expression of ESR1 in the neonatal rat hypothalamus results in lasting changes in ESR1 expression through the juvenile period, and can “rescue” hormone receptor levels and behavior of offspring reared by low LG dams, potentially mediated by downstream alterations within reward circuitry. Thus, the transmission of maternal behavior from one generation to the next can be augmented by neonatal ERα in the MPOA.
doi:10.1002/dneu.22206
PMCID: PMC4284154  PMID: 25044746
maternal care; estrogen receptor-alpha; medial preoptic area; ventral tegmental area; dopamine
13.  Development of echolocation calls and neural selectivity for echolocation calls in the pallid bat 
Developmental neurobiology  2014;75(10):1125-1139.
Studies of birdsongs and neural selectivity for songs have provided important insights into principles of concurrent behavioral and auditory system development. Relatively little is known about mammalian auditory system development in terms of vocalizations, or other behaviorally relevant sounds. This review suggests echolocating bats are suitable mammalian model systems to understand development of auditory behaviors. The simplicity of echolocation calls with known behavioral relevance and strong neural selectivity provides a platform to address how natural experience shapes cortical receptive field (RF) mechanisms. We summarize recent studies in the pallid bat that followed development of echolocation calls and cortical processing of such calls. We also discuss similar studies in the mustached bat for comparison. These studies suggest: (1) there are different developmental sensitive periods for different acoustic features of the same vocalization. The underlying basis is the capacity for some components of the RF to be modified independent of others. Some RF computations and maps involved in call processing are present even before the cochlea is mature and well before use of echolocation in flight. Others develop over a much longer time course. (2) Normal experience is required not just for refinement, but also for maintenance, of response properties that develop in an experience independent manner. (3) Experience utilizes millisecond range changes in timing of inhibitory and excitatory RF components as substrates to shape vocalization selectivity. We suggest that bat species and call diversity provide a unique opportunity to address developmental constraints in the evolution of neural mechanisms of vocalization processing.
doi:10.1002/dneu.22226
PMCID: PMC4336241  PMID: 25142131
development; receptive fields; spectrotemporal processing; auditory cortex; vocalizations
14.  Effects of COX inhibition and LPS on Formalin Induced Pain in the Infant Rat 
Developmental neurobiology  2014;75(10):1068-1079.
In the adult, immune and neural processes jointly modulate pain. During development, both are in transition and little is known about the role that the immune system plays in pain processing in infants and children. The objective of this study was to determine if inhibition or augmentation of the immune system would alter pain processing in the infant rat, as it does in the adult. In Experiment 1, rat pups aged 3, 10 or 21 (PN3, PN10, PN21) days of age were pre-treated with NS398 (selective COX-2 inhibitor) or SC560 (selective COX-1 inhibitor) and tested in the intraplantar formalin test to assess effects of COX inhibition on nociception. Neither drug had an effect on the behavioral response at PN3 or PN10 pups but both drugs attenuated nociceptive scores in PN21 pups. cFos expression in the spinal cord likewise was reduced only at PN21. In Experiment 2, pups were injected with LPS prior to the formalin test at PN3 and PN21. LPS increased the nociceptive response more robustly at PN21 than at PN3, while increasing cytokine mRNA equally at both ages. The augmentation of pain responding at PN21 was largely during the late stages of the formalin test, as reported in the adult. These data support previous findings demonstrating late maturing immune modulation of nociceptive behaviors.
doi:10.1002/dneu.22230
PMCID: PMC4362925  PMID: 25205468
15.  Visual development in primates: Neural mechanisms and critical periods 
Developmental neurobiology  2015;75(10):1080-1090.
Despite many decades of research into the development of visual cortex, it remains unclear what neural processes set limitations on the development of visual function and define its vulnerability to abnormal visual experience. This selected review examines the development of visual function and its neural correlates, and highlights the fact that in most cases receptive field properties of infant neurons are substantially more mature than infant visual function. One exception is temporal resolution, which can be accounted for by resolution of neurons at the level of the LGN. In terms of spatial vision, properties of single neurons alone are not sufficient to account for visual development. Different visual functions develop over different time courses. Their onset may be limited by the existence of neural response properties that support a given perceptual ability, but the subsequent time course of maturation to adult levels remains unexplained. Several examples are offered suggesting that taking account of weak signaling by infant neurons, correlated firing, and pooled responses of populations of neurons brings us closer to an understanding of the relationship between neural and behavioral development.
doi:10.1002/dneu.22276
PMCID: PMC4523497  PMID: 25649764
Visual development; visual cortex; critical period; extrastriate cortex
16.  miR‐181a/b control the assembly of visual circuitry by regulating retinal axon specification and growth 
Developmental Neurobiology  2015;75(11):1252-1267.
ABSTRACT
Connectivity and function of neuronal circuitry require the correct specification and growth of axons and dendrites. Here, we identify the microRNAs miR‐181a and miR‐181b as key regulators of retinal axon specification and growth. Loss of miR‐181a/b in medaka fish (Oryzias latipes) failed to consolidate amacrine cell processes into axons and delayed the growth of retinal ganglion cell (RGC) axons. These alterations were accompanied by defects in visual connectivity and function. We demonstrated that miR‐181a/b exert these actions through negative modulation of MAPK/ERK signaling that in turn leads to RhoA reduction and proper neuritogenesis in both amacrine cells and RGCs via local cytoskeletal rearrangement. Our results identify a new pathway for axon specification and growth unraveling a crucial role of miR‐181a/b in the proper establishment of visual system connectivity and function. © 2015 Wiley Periodicals, Inc. Develop Neurobiol 75: 1252–1267, 2015
doi:10.1002/dneu.22282
PMCID: PMC5033011  PMID: 25728313
miR‐181a; miR‐181b; axon specification; retina; MAPK signaling
17.  Development of the stria vascularis and potassium regulation in the human fetal cochlea: Insights into hereditary sensorineural hearing loss 
Developmental Neurobiology  2015;75(11):1219-1240.
ABSTRACT
Sensorineural hearing loss (SNHL) is one of the most common congenital disorders in humans, afflicting one in every thousand newborns. The majority is of heritable origin and can be divided in syndromic and nonsyndromic forms. Knowledge of the expression profile of affected genes in the human fetal cochlea is limited, and as many of the gene mutations causing SNHL likely affect the stria vascularis or cochlear potassium homeostasis (both essential to hearing), a better insight into the embryological development of this organ is needed to understand SNHL etiologies. We present an investigation on the development of the stria vascularis in the human fetal cochlea between 9 and 18 weeks of gestation (W9–W18) and show the cochlear expression dynamics of key potassium‐regulating proteins. At W12, MITF+/SOX10+/KIT+ neural‐crest‐derived melanocytes migrated into the cochlea and penetrated the basement membrane of the lateral wall epithelium, developing into the intermediate cells of the stria vascularis. These melanocytes tightly integrated with Na+/K+‐ATPase‐positive marginal cells, which started to express KCNQ1 in their apical membrane at W16. At W18, KCNJ10 and gap junction proteins GJB2/CX26 and GJB6/CX30 were expressed in the cells in the outer sulcus, but not in the spiral ligament. Finally, we investigated GJA1/CX43 and GJE1/CX23 expression, and suggest that GJE1 presents a potential new SNHL associated locus. Our study helps to better understand human cochlear development, provides more insight into multiple forms of hereditary SNHL, and suggests that human hearing does not commence before the third trimester of pregnancy. © 2015 Wiley Periodicals, Inc. Develop Neurobiol 75: 1219–1240, 2015
doi:10.1002/dneu.22279
PMCID: PMC5024031  PMID: 25663387
human; sensorineural hearing loss; development; stria vascularis; melanocytes
18.  Melanopsin ganglion cells extend dendrites into the outer retina during early postnatal development 
Developmental neurobiology  2015;75(9):935-946.
Melanopsin ganglion cells express the photopigment melanopsin and are the first functional photoreceptors to develop in the mammalian retina. They have been shown to play a variety of important roles in visual development and behavior in the early postnatal period (Johnson et al., 2010; Kirkby and Feller, 2013; Rao et al., 2013; Renna et al., 2011). Here, we probed the maturation of the dendritic arbors of melanopsin ganglion cells during this developmental period in mice. We found that some melanopsin ganglion cells (mainly the M1-subtype) transiently extend their dendrites not only into the inner plexiform layer (where they receive synaptic inputs from bipolar and amacrine cells) but also into the outer plexiform layer, where in mature retina, rod and cone photoreceptors are thought to contact only bipolar and horizontal cells. Thus, some immature melanopsin ganglion cells are biplexiform. This feature is much less common though still present in the mature retina. It reaches peak incidence 8–12 days after birth, before the eyes open and bipolar cells are sufficiently mature to link rods and cones to ganglion cells. At this age, some outer dendrites of melanopsin ganglion cells lie in close apposition to the axon terminals of cone photoreceptors and express a postsynaptic marker of glutamatergic transmission, postsynaptic density-95 protein (PSD-95). These findings raise the possibility of direct, monosynaptic connections between cones and melanopsin ganglion cells in the early postnatal retina. We provide a detailed description of the developmental profile of these processes and consider their possible functional and evolutionary significance.
doi:10.1002/dneu.22260
PMCID: PMC4478280  PMID: 25534911
melanopsin; ipRGC; biplexiform; ganglion cell; retina
19.  Zebrafish cerebrospinal fluid mediates cell survival through a retinoid signaling pathway 
Developmental Neurobiology  2015;76(1):75-92.
ABSTRACT
Cerebrospinal fluid (CSF) includes conserved factors whose function is largely unexplored. To assess the role of CSF during embryonic development, CSF was repeatedly drained from embryonic zebrafish brain ventricles soon after their inflation. Removal of CSF increased cell death in the diencephalon, indicating a survival function. Factors within the CSF are required for neuroepithelial cell survival as injected mouse CSF but not artificial CSF could prevent cell death after CSF depletion. Mass spectrometry analysis of the CSF identified retinol binding protein 4 (Rbp4), which transports retinol, the precursor to retinoic acid (RA). Consistent with a role for Rbp4 in cell survival, inhibition of Rbp4 or RA synthesis increased neuroepithelial cell death. Conversely, ventricle injection of exogenous human RBP4 plus retinol, or RA alone prevented cell death after CSF depletion. Zebrafish rbp4 is highly expressed in the yolk syncytial layer, suggesting Rbp4 protein and retinol/RA precursors can be transported into the CSF from the yolk. In accord with this suggestion, injection of human RBP4 protein into the yolk prevents neuroepithelial cell death in rbp4 loss‐of‐function embryos. Together, these data support the model that Rbp4 and RA precursors are present within the CSF and used for synthesis of RA, which promotes embryonic neuroepithelial survival. © 2015 Wiley Periodicals, Inc. Develop Neurobiol 76: 75–92, 2016
doi:10.1002/dneu.22300
PMCID: PMC4644717  PMID: 25980532
cerebrospinal fluid; retinoic acid; cell survival; brain development; RBP4
20.  The Dynein Inhibitor Ciliobrevin D Inhibits the Bi-directional Transport of Organelles along Sensory Axons and Impairs NGF-Mediated Regulation of Growth Cones and Axon Branches 
Developmental neurobiology  2014;75(7):757-777.
The axonal transport of organelles is critical for the development, maintenance and survival of neurons, and its dysfunction has been implicated in several neurodegenerative diseases. Retrograde axon transport is mediated by the motor protein dynein. In this study, using embryonic chicken dorsal root ganglion neurons, we investigate the effects of Ciliobrevin D, a pharmacological dynein inhibitor, on the transport of axonal organelles, axon extension, nerve growth factor (NGF)-induced branching and growth cone expansion, and axon thinning in response to actin filament depolymerization. Live imaging of mitochondria, lysosomes and Golgi-derived vesicles in axons revealed that both the retrograde and anterograde transport of these organelles was inhibited by treatment with Ciliobrevin D. Treatment with Ciliobrevin D reversibly inhibits axon extension and transport, with effects detectable within the first 20 minutes of treatment. NGF induces growth cone expansion, axonal filopodia formation and branching. Ciliobrevin D prevented NGF-induced formation of axonal filopodia and branching but not growth cone expansion. Finally, we report that the retrograde reorganization of the axonal cytoplasm which occurs upon actin filament depolymerization is inhibited by treatment with Ciliobrevin D, indicating a role for microtubule based transport in this process, as well as Ciliobrevin D accelerating Wallerian degeneration. This study identifies Ciliobrevin D as an inhibitor of the bi-directional transport of multiple axonal organelles, indicating this drug may be a valuable tool for both the study of dynein function and a first pass analysis of the role of axonal transport.
doi:10.1002/dneu.22246
PMCID: PMC4436090  PMID: 25404503
Ciliobrevin D; axon transport; axon growth; axon branching; dynein; kinesin; mitochondria; lysosome; Golgi derived vesicles; latrunculin; Wallerian degeneration; tubulin tyrosination; tubulin acetylation; p150glued dynactin
21.  Ephrin-As are required for the topographic mapping but not laminar choice of physiologically distinct RGC types 
Developmental neurobiology  2015;75(6):584-593.
In the retinocollicular projection, the axons from functionally distinct retinal ganglion cell (RGC) types form synapses in a stereotypical manner along the superficial to deep axis of the SC. Each lamina contains an orderly topographic map of the visual scene but different laminae receive inputs from distinct sets of RGCs, and inputs to each lamina are aligned with the others to integrate parallel streams of visual information. To determine the relationship between laminar organization and topography of physiologically defined RGC types, we used genetic and anatomical axon tracing techniques in wild type and ephrin-A mutant mice. We find that adjacent RGCs of the same physiological type can send axons to both ectopic and normal topographic locations, supporting a penetrance model for ephrin-A independent mapping cues. While the overall laminar organization in the SC is unaffected in ephrin-A2/A5 double mutant mice, analysis of the laminar locations of ectopic terminations shows that the topographic maps of different RGC types are misaligned. These data lend support to the hypothesis that the retinocollicular projection is a superimposition of a number of individual 2-D topographic maps that originate from specific types of RGCs, require ephrin-A signaling, and form independently of the other maps.
doi:10.1002/dneu.22265
PMCID: PMC4437846  PMID: 25649160
22.  Spatial pattern of spontaneous retinal waves instructs retinotopic map refinement more than activity frequency 
Developmental neurobiology  2015;75(6):621-640.
Spontaneous activity during early development is necessary for the formation of precise neural connections, but it remains uncertain whether activity plays an instructive or permissive role in brain wiring. In the visual system, retinal ganglion cell (RGC) projections to the brain form two prominent sensory maps, one reflecting eye of origin and the other retinotopic location. Recent studies provide compelling evidence supporting an instructive role for spontaneous retinal activity in the development of eye-specific projections, but evidence for a similarly instructive role in the development of retinotopy is more equivocal. Here, we report on experiments in which we knocked down the expression of β2-containing nicotinic acetylcholine receptors (β2-nAChRs) specifically in the retina through a Cre-loxP recombination strategy. Overall levels of spontaneous retinal activity in retina-specific β2-nAChR mutant mice (Rx-β2cKO), examined in vitro and in vivo, were reduced to a degree comparable to that observed in whole animal β2-nAChR mouse mutants (β2KO). However, many residual spontaneous waves in Rx-β2cKO mice displayed local propagating features with strong correlations between nearby but not distant RGCs typical of waves observed in WT, but not β2KO mice. We further observed that eye-specific segregation was disrupted in Rx-β2cKO mice, but retinotopy was spared in a competition-dependent manner. These results suggest that propagating patterns of spontaneous retinal waves are essential for normal development of the retinotopic map, even while overall activity levels are significantly reduced, and support an instructive role for spontaneous retinal activity in both eye-specific segregation and retinotopic refinement.
doi:10.1002/dneu.22288
PMCID: PMC4697738  PMID: 25787992
23.  Mini-review: Making scent of the presence and local translation of odorant receptor mRNAs in olfactory axons 
Developmental neurobiology  2013;74(3):259-268.
Rodents contain in their genome more than 1,000 functional odorant receptor genes, which are specifically expressed by the olfactory sensory neurons projecting from the olfactory epithelium to the olfactory bulb. Strong evidence for the presence and local translation of odorant receptor mRNAs in the axon of olfactory sensory neurons was obtained, but no function has been assigned to these axonal mRNAs yet. The aim of this review is to discuss the evidence for the presence and local translation of odorant receptor mRNAs in olfactory sensory axons, and to speculate on their possible function in the wiring of the mouse olfactory sensory projections.
doi:10.1002/dneu.22122
PMCID: PMC4879812  PMID: 23959692
24.  The role of cell adhesion molecules in visual circuit formation: From neurite outgrowth to maps and synaptic specificity 
Developmental Neurobiology  2015;75(6):569-583.
ABSTRACT
The formation of visual circuitry is a multistep process that involves cell–cell interactions based on a range of molecular mechanisms. The correct implementation of individual events, including axon outgrowth and guidance, the formation of the topographic map, or the synaptic targeting of specific cellular subtypes, are prerequisites for a fully functional visual system that is able to appropriately process the information captured by the eyes. Cell adhesion molecules (CAMs) with their adhesive properties and their high functional diversity have been identified as key actors in several of these fundamental processes. Because of their growth‐promoting properties, CAMs play an important role in neuritogenesis. Furthermore, they are necessary to control additional neurite development, regulating dendritic spacing and axon pathfinding. Finally, trans‐synaptic interactions of CAMs ensure cell type‐specific connectivity as a basis for the establishment of circuits processing distinct visual features. Recent discoveries implicating CAMs in novel mechanisms have led to a better general understanding of neural circuit formation, but also revealed an increasing complexity of their function. This review aims at describing the different levels of action for CAMs to shape neural connectivity, with a special focus on the visual system. © 2015 Wiley Periodicals, Inc. Develop Neurobiol 75: 569–583, 2015
doi:10.1002/dneu.22267
PMCID: PMC4855686  PMID: 25649254
cell adhesion molecules; visual system; topographic map; axon pathfinding; synaptic targeting
25.  The RanGEF Bj1 promotes Prospero nuclear export and neuroblast self-renewal 
Developmental neurobiology  2014;75(5):485-493.
Drosophila larval neuroblasts are a model system for studying stem cell self-renewal and differentiation. Here we report a novel role for the Drosophila gene Bj1 in promoting larval neuroblast self-renewal. Bj1 is the guanine-nucleotide exchange factor for Ran GTPase, which regulates nuclear import/export. Bj1 transcripts are highly enriched in larval brain neuroblasts (in both central brain and optic lobe), while Bj1 protein is detected in both neuroblasts and their neuronal progeny. Loss of Bj1 using both mutants or RNAi causes a progressive loss of larval neuroblasts, showing that Bj1 is required to maintain neuroblast numbers. Loss of Bj1 does not result in neuroblast apoptosis, but rather leads to abnormal nuclear accumulation of the differentiation factor Prospero, and premature neuroblast differentiation. We conclude that the Bj1 RanGEF promotes Prospero nuclear export and neuroblast self-renewal.
doi:10.1002/dneu.22237
PMCID: PMC4397115  PMID: 25312250

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