Inhibitory and excitatory subtypes of cochlear nucleus neurons are defined by distinct bHLH transcription factors, Ptf1a and Atoh1

Fujiyama, Tomoyuki; Yamada, Mayumi; Terao, Mineko; Terashima, Toshio; Hioki, Hiroyuki; Inoue, Yukiko; Inoue, Tohru; Masuyama, Norihisa; Obata, Kunihiko; Yanagawa, Yuchio; Kawaguchi, Yoshiya; Nabeshima, Yo‐ichi; Hoshino, Mikio

doi:10.1242/dev.033480

Cited by 111 publications

(156 citation statements)

References 76 publications

(117 reference statements)

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“…2A). To test the functional significance of individual Plexin-B2-mediated signaling pathways in the developing cerebellum, we crossed mice carrying floxed alleles of Plexin-B2 (plxnb2 flox/flox ) with mice expressing Cre specifically in cerebellar granule cell precursor cells under the control of the Atoh1 promoter (Atoh1-Cre; plxnb2 flox/flox ) (23,37). These mice phenocopied the cerebellar abnormalities observed in surviving plxnb2 global knockout mice (Fig.…”

Section: Resultsmentioning

confidence: 99%

Genetic dissection of plexin signaling in vivo

Worzfeld

Swiercz

Sentürk

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Mammalian plexins constitute a family of transmembrane receptors for semaphorins and represent critical regulators of various processes during development of the nervous, cardiovascular, skeletal, and renal system. In vitro studies have shown that plexins exert their effects via an intracellular R-Ras/M-Ras GTPase-activating protein (GAP) domain or by activation of RhoA through interaction with Rho guanine nucleotide exchange factor proteins. However, which of these signaling pathways are relevant for plexin functions in vivo is largely unknown. Using an allelic series of transgenic mice, we show that the GAP domain of plexins constitutes their key signaling module during development. Mice in which endogenous Plexin-B2 or Plexin-D1 is replaced by transgenic versions harboring mutations in the GAP domain recapitulate the phenotypes of the respective null mutants in the developing nervous, vascular, and skeletal system. We further provide genetic evidence that, unexpectedly, the GAP domain-mediated developmental functions of plexins are not brought about via R-Ras and M-Ras inactivation. In contrast to the GAP domain mutants, Plexin-B2 transgenic mice defective in Rho guanine nucleotide exchange factor binding are viable and fertile but exhibit abnormal development of the liver vasculature. Our genetic analyses uncover the in vivo contextdependence and functional specificity of individual plexin-mediated signaling pathways during development.neural tube | cerebellum | outflow tract P lexins constitute a family of transmembrane proteins that serve as receptors for semaphorins (1). They function as key regulators of a multitude of developmental processes, including axon guidance, pattern and synapse formation in the nervous system (2), vasculogenesis and angiogenesis (3, 4), and morphogenesis of the heart, kidney, and skeletal system (5). In the adult organism, plexins play crucial roles in the physiology and pathophysiology of the immune and cardiovascular system, as well as in bone homeostasis and in cancer (6-9). Nine plexins have been identified in the mammalian system, which are grouped into four subfamilies, A-D, according to sequence homologies.The activation of plexins by their semaphorin ligands triggers several intracellular signaling cascades, most of which modulate the activity of small GTPases (10). The intracellular domain of all plexins shares homology with GTPase-activating proteins (GAPs) and confers the deactivation of R-Ras, M-Ras, and Rap1 (11-17). The GAP activity toward R-Ras and M-Ras, but not toward Rap1, requires binding of Rnd GTPases to the plexin receptor (11,12,15,16). Plexins of the B-subfamily differ from all other plexins in that they carry a C-terminal PDZ domain interaction motif that mediates a stable interaction with the Rho guanine nucleotide exchange factor (RhoGEF) proteins . Activation of B-plexins by semaphorin ligands results in activation of the RhoGEF proteins and subsequent activation of . This process and the GAP function of B-plexins are independent of each other, becau...

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Section: Resultsmentioning

confidence: 99%

Genetic dissection of plexin signaling in vivo

Worzfeld

Swiercz

Sentürk

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…1 K-N ), a known Atoh1-expressing site (Akazawa et al, 1995;Wang et al, 2005), and a stream of cells at its lateral edge ( Fig. 1 N) that may correspond to the forming cochlear nucleus, a rhombic lip derivative Fujiyama et al, 2009). In the ventral medulla, Atoh1 thus is a specific marker of RTN neurons defined as cells expressing Phox2b, Vglut2, and NK1R but not TH.…”

Section: E-g) (Since Nk1rmentioning

confidence: 99%

Defective Respiratory Rhythmogenesis and Loss of Central Chemosensitivity in Phox2b Mutants Targeting Retrotrapezoid Nucleus Neurons

Dubreuil¹,

Thoby‐Brisson²,

Rallu³

et al. 2009

J. Neurosci.

123

165

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The retrotrapezoid nucleus (RTN) is a group of neurons in the rostral medulla, defined here as Phox2b-, Vglut2-, neurokinin1 receptor-, and Atoh1-expressing cells in the parafacial region, which have been proposed to function both as generators of respiratory rhythm and as central respiratory chemoreceptors. The present study was undertaken to assess these two putative functions using genetic tools. We generated two conditional Phox2b mutations, which target different subsets of Phox2b-expressing cells, but have in common a massive depletion of RTN neurons. In both conditional mutants as well as in the previously described Phox2b 27Ala mutants, in which the RTN is also compromised, the respiratory-like rhythmic activity normally seen in the parafacial region of fetal brainstem preparations was completely abrogated. Rhythmic motor bursts were recorded from the phrenic nerve roots in the mutants, but their frequency was markedly reduced. Both the rhythmic activity in the RTN region and the phrenic nerve discharges responded to a low pH challenge in control, but not in the mutant embryos. Together, our results provide genetic evidence for the essential role of the Phox2b-expressing RTN neurons both in establishing a normal respiratory rhythm before birth and in providing chemosensory drive.

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“…The basic helix-loop-helix (bHLH) transcription factor Atoh1 is expressed in the dorsal-most RL in a subset of interneuron progenitors, termed dA1 (Akazawa et al, 1995;Ben-Arie et al, 1997;Wang et al, 2005 Fujiyama et al, 2009). However, knowledge is buffer, washed with PBS and incubated in PBS with 0.1% Tween20 (PBT)/ 5% goat serum for 2 h, before incubation for ON with the following antibodies: Pax2 (1:50, Abcam), Brn3a and 3A10 (both 1:50, Developmental Studies Hybridoma Bank), Myc (1:500, Santa Cruz Biotechnology).…”

Section: Introductionmentioning

confidence: 99%

Axonal Patterns and Targets of dA1 Interneurons in the Chick Hindbrain

Kohl

Hadas²,

Klar³

et al. 2012

J. Neurosci.

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Hindbrain dorsal interneurons that comprise the rhombic lip relay sensory information and coordinate motor outputs. The progenitor dA1 subgroup of interneurons, which is formed along the dorsal-most region of the caudal rhombic lip, gives rise to the cochlear and precerebellar nuclei. These centers project sensory inputs toward upper-brain regions. The fundamental role of dA1 interneurons in the assembly and function of these brainstem nuclei is well characterized. However, the precise en route axonal patterns and synaptic targets of dA1 interneurons are not clear as of yet. Novel genetic tools were used to label dA1 neurons and trace their axonal trajectories and synaptic connections at various stages of chick embryos. Using dA1-specific enhancers, two contralateral ascending axonal projection patterns were identified; one derived from rhombomeres 6 -7 that elongated in the dorsal funiculus, while the other originated from rhombomeres 2-5 and extended in the lateral funiculus. Targets of dA1 axons were followed at later stages using PiggyBac-mediated DNA transposition. dA1 axons were found to project and form synapses in the auditory nuclei and cerebellum. Investigation of mechanisms that regulate the patterns of dA1 axons revealed a fundamental role of Lim-homeodomain (HD) proteins. Switch in the expression of the specific dA1 Lim-HD proteins Lhx2/9 into Lhx1, which is typically expressed in dB1 interneurons, modified dA1 axonal patterns to project along the routes of dB1 subgroup. Together, the results of this research provided new tools and knowledge to the assembly of trajectories and connectivity of hindbrain dA1 interneurons and of molecular mechanisms that control these patterns.

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Inhibitory and excitatory subtypes of cochlear nucleus neurons are defined by distinct bHLH transcription factors, Ptf1a and Atoh1

Cited by 111 publications

References 76 publications

Genetic dissection of plexin signaling in vivo

Genetic dissection of plexin signaling in vivo

Defective Respiratory Rhythmogenesis and Loss of Central Chemosensitivity in Phox2b Mutants Targeting Retrotrapezoid Nucleus Neurons

Axonal Patterns and Targets of dA1 Interneurons in the Chick Hindbrain

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