The Tumor Suppressor Gene Retinoblastoma-1 Is Required for Retinotectal Development and Visual Function in Zebrafish

Gyda, Michael; Wolman, Marc A.; Lorent, Kristin; Granato, Michael

doi:10.1371/journal.pgen.1003106

Cited by 34 publications

(30 citation statements)

References 34 publications

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“…Embryos/larvae were maintained on a 14/10 hour light/dark cycle at 29°C and raised as previously described (Gyda et al, 2012; Kimmel et al, 1995). Behavioral experiments were conducted on 5-12 dpf larvae.…”

Section: Methodsmentioning

confidence: 99%

A Genome-wide Screen Identifies PAPP-AA-Mediated IGFR Signaling as a Novel Regulator of Habituation Learning

Wolman

Jain

Marsden

et al. 2015

Neuron

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102

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Summary Habituation represents a fundamental form of learning, yet the underlying molecular genetic mechanisms are not well defined. Here we report on a genome-wide genetic screen, coupled with whole genome sequencing, that identified 14 zebrafish startle habituation mutants including mutants of the vertebrate specific gene pregnancy associated plasma protein-aa (pappaa). PAPP-AA encodes an extracellular metalloprotease known to increase IGF bioavailability thereby enhancing IGF receptor signaling. We find that pappaa is expressed by startle circuit neurons, and expression of wildtype, but not a metalloprotease-inactive version of pappaa restores habituation in pappaa mutants. Furthermore, acutely inhibiting IGF1R function in wild-type reduces habituation, while activation of IGF1R downstream effectors in pappaa mutants restores habituation, demonstrating that pappaa promotes learning by acutely and locally increasing IGF bioavailability. In sum, our results define the first functional gene set for habituation learning in a vertebrate, and identify PAPPAA-regulated IGF signaling as a novel mechanism regulating habituation learning.

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Section: Methodsmentioning

confidence: 99%

A Genome-wide Screen Identifies PAPP-AA-Mediated IGFR Signaling as a Novel Regulator of Habituation Learning

Wolman

Jain

Marsden

et al. 2015

Neuron

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102

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“…Based on these studies, spiral fiber neurons are well positioned to influence the M-cell mediated escape behavior. In fact, mutants for the retinoblastoma-1 gene that have defects in axon targeting, including in the spiral fiber neurons, display abnormal turning movements in response to touch [13, 14]. However, the stimuli that drive the spiral fiber neurons have yet to be identified, and their role in the M-cell escape network remains unclear.…”

Section: Resultsmentioning

confidence: 99%

A Convergent and Essential Interneuron Pathway for Mauthner-Cell-Mediated Escapes

et al. 2015

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The Mauthner cell (M-cell) is a command-like neuron in teleost fish whose firing in response to aversive stimuli is correlated with short-latency escapes [1-3]. M-cells have been proposed as evolutionary ancestors of startle response neurons of the mammalian reticular formation [4], and studies of this circuit have uncovered important principles in neurobiology that generalize to more complex vertebrate models [3]. The main excitatory input was thought to originate from multisensory afferents synapsing directly onto the M-cell dendrites [3]. Here, we describe an additional, convergent pathway that is essential for the M-cell-mediated startle behavior in larval zebrafish. It is composed of excitatory interneurons called spiral fiber neurons, which project to the M-cell axon hillock. By in vivo calcium imaging, we found that spiral fiber neurons are active in response to aversive stimuli capable of eliciting escapes. Like M-cell ablations, bilateral ablations of spiral fiber neurons largely eliminate short-latency escapes. Unilateral spiral fiber neuron ablations shift the directionality of escapes and indicate that spiral fiber neurons excite the M-cell in a lateralized manner. Their optogenetic activation increases the probability of short-latency escapes, supporting the notion that spiral fiber neurons help activate M-cell-mediated startle behavior. These results reveal that spiral fiber neurons are essential for the function of the M-cell in response to sensory cues and suggest that convergent excitatory inputs that differ in their input location and timing ensure reliable activation of the M-cell, a feedforward excitatory motif that may extend to other neural circuits

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“…TUNEL staining was performed as previously described (Lowery and Sive, 2005) using Apoptag Peroxidase In Situ Apoptosis Detection Kit (Chemicon Cat# S7100). Anti-DIG-POD antibody (Roche) and Tyramide Signal Amplification (PerkinElmer) were used to detect TUNEL-positive nuclei (Gyda et al, 2012). mRNA injections mRNA was transcribed from linearized expression constructs using the SP6 mMessage mMachine kit (Ambion).…”

Section: Immunohistochemistrymentioning

confidence: 99%

Zebrafish foxc1a drives appendage-specific neural circuit development

et al. 2015

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Neural connectivity between the spinal cord and paired appendages is key to the superior locomotion of tetrapods and aquatic vertebrates. In contrast to nerves that innervate axial muscles, those innervating appendages converge at a specialized structure, the plexus, where they topographically reorganize before navigating towards their muscle targets. Despite its importance for providing appendage mobility, the genetic program that drives nerve convergence at the plexus, as well as the functional role of this convergence, are not well understood. Here, we show that in zebrafish the transcription factor foxc1a is dispensable for trunk motor nerve guidance but is required to guide spinal nerves innervating the pectoral fins, equivalent to the tetrapod forelimbs. In foxc1a null mutants, instead of converging with other nerves at the plexus, pectoral fin nerves frequently bypass the plexus. We demonstrate that foxc1a expression in muscle cells delineating the nerve path between the spinal cord and the plexus region restores convergence at the plexus. By labeling individual fin nerves, we show that mutant nerves bypassing the plexus enter the fin at ectopic positions, yet innervate their designated target areas, suggesting that motor axons can select their appropriate fin target area independently of their migration through the plexus. Although foxc1a mutants display topographically correct fin innervation, mutant fin muscles exhibit a reduction in the levels of pre-and postsynaptic structures, concomitant with reduced pectoral fin function. Combined, our results reveal foxc1a as a key player in the development of connectivity between the spinal cord and paired appendages, which is crucial for appendage mobility.

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The Tumor Suppressor Gene Retinoblastoma-1 Is Required for Retinotectal Development and Visual Function in Zebrafish

Cited by 34 publications

References 34 publications

A Genome-wide Screen Identifies PAPP-AA-Mediated IGFR Signaling as a Novel Regulator of Habituation Learning

A Genome-wide Screen Identifies PAPP-AA-Mediated IGFR Signaling as a Novel Regulator of Habituation Learning

A Convergent and Essential Interneuron Pathway for Mauthner-Cell-Mediated Escapes

Zebrafish foxc1a drives appendage-specific neural circuit development

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