The Transcription Factor Bhlhb4 Is Required for Rod Bipolar Cell Maturation

Bramblett, Debra E.; Pennesi, Mark E.; Wu, Samuel M.; Tsai, Ming Jer

doi:10.1016/j.neuron.2004.08.032

Cited by 97 publications

(125 citation statements)

References 42 publications

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“…(i) All three mutant mouse strains have been extensively studied and used by many research groups. There is little detectable neuronal degeneration (6,21,22), and thus, degeneration-induced rewiring should not occur in these mice.…”

Section: Discussionmentioning

confidence: 99%

“…In addition to studying rod/cone inputs to DBCs by using the response sensitivity and paired light protocols in wild-type mice, we take advantage of several pathway-specific knockout-mouse models to verify the relative contributions of rod and cone as well as the primary, secondary, and tertiary rod/cone pathways to DBC light responses. The mouse models include mice that lack rod response (rod transducin knockout [Trα −/− ]) (21), mice that lack the connexin36 gap-junction protein (Cx36 −/− ) (6), and mice that lack DBC R s (Bhlhb4 −/− ) (22). Results obtained suggest that subpopulations of DBC R s receive direct synaptic inputs from cones and subpopulations of DBC C s receive direct synaptic inputs from rods.…”

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confidence: 99%

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Direct rod input to cone BCs and direct cone input to rod BCs challenge the traditional view of mammalian BC circuitry

Pang

Gao

Lem

et al. 2009

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

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132

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Bipolar cells are the central neurons of the retina that transmit visual signals from rod and cone photoreceptors to third-order neurons in the inner retina and the brain. A dogma set forth by early anatomical studies is that bipolar cells in mammalian retinas receive segregated rod/cone synaptic inputs (either from rods or from cones), and here, we present evidence that challenges this traditional view. By analyzing light-evoked cation currents from morphologically identified depolarizing bipolar cells (DBCs) in the wild-type and three pathway-specific knockout mice (rod transducin knockout [Trα], and transcription factor beta4 knockout [Bhlhb4, we show that a subpopulation of rod DBCs (DBC R2 s) receives substantial input directly from cones and a subpopulation of cone DBCs (DBC C1 s) receives substantial input directly from rods. These results provide evidence of the existence of functional rod-DBC C and cone-DBC R synaptic pathways in the mouse retina as well as the previously proposed rod hyperpolarizing bipolar-cells pathway. This is grounds for revising the mammalian rod/cone bipolar cell dogma.light-evoked cation and chloride currents | axon-terminal stratification | connexin36 | wild-type and mutant mice | depolarizing bipolar cell I n the visual system, rod photoreceptors register dim light signals, and cone photoreceptors encode brighter light signals (1). Bipolar cells (BCs) are the second-order neurons in the retina that receive light-elicited signals from rod and cone photoreceptors and transmit them to amacrine cells (ACs) and ganglion cells (GCs) in the inner retina (1, 2). Early anatomical studies have shown that mammalian rods make synaptic contacts with only one type of bipolar cell, the rod depolarizing bipolar cell (DBC R ), whereas cones make synaptic contacts with eight to nine types of cone depolarizing (DBC C s) or hyperpolarizing bipolar cells (HBC C s) (3-5). Additionally, DBC R s do not make output synapses directly on GCs, the output neurons of the retina, but on the AII amacrine cells (AIIACs), which make electrical synapses (with connexin36 at least at the AIIAC side) (6, 7) with DBC C s (that send signals to ON GCs) and inhibitory glycinergic synapses with HBC C s and OFF GCs (8-10). Therefore, in addition to direct cone synaptic inputs, DBC C s receive rod-mediated signals from AIIAC-DBC C electrical synapses, and HBC C s receive rod-mediated signals from the AIIAC-HBC C chemical synapses (11,12). This AIIAC-mediated rod/cone signal mixing is named the primary rod-to-cone signaling pathway (13). Furthermore, rods and cones are electrically coupled with each other, possibly through connexin36-mediated gap junctions (6,14,15), and such rod/cone-signal mixing at the photoreceptor level is named the secondary rod-cone pathway (13).The rod and cone bipolar cell-signaling circuitry described above has been considered for many years as the general organizational plan (to a certain degree as the dogma) for all mammals (3,5,16). Evidence from recent studies, however, begins to challenge t...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Direct rod input to cone BCs and direct cone input to rod BCs challenge the traditional view of mammalian BC circuitry

Pang

Gao

Lem

et al. 2009

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

Self Cite

132

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“…As expected, Jmjd3 expression significantly decreased. Bhlhb4 is essential for the maturation of rod-ON-BP cells, which were labeled for PKC (23), and Vsx1 plays a pivotal role in the differentiation of cone-OFF-BP Fig. 2.…”

Section: Significancementioning

confidence: 99%

Histone demethylase Jmjd3 is required for the development of subsets of retinal bipolar cells

Iida

Iwagawa

Kuribayashi

et al. 2014

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

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Di-and trimethylation of lysine 27 on histone H3 (H3K27me2/3) is an important gene repression mechanism. H3K27me2/3-specific demethylase, Jmjd3, was expressed in the inner nuclear layer during late retinal development. In contrast, H3K27 methyltransferase, Ezh2, was highly expressed in the embryonic retina but its expression decreased rapidly after birth. Jmjd3 loss of function in the developing retina resulted in failed differentiation of PKC-positive bipolar cell subsets (rod-ON-BP) and reduced transcription factor Bhlhb4 expression, which is critical for the differentiation of rod-ON-BP cells. Overexpression of Bhlhb4, but not of other BP cell-related genes, such as transcription factors Neurod and Chx10, in Jmjd3-knockdown retina rescued loss of PKC-positive BP cells. Populations of other retinal cell subsets were not significantly affected. In addition, proliferation activity and apoptotic cell number during retinal development were not affected by the loss of Jmjd3. Levels of histone H3 trimethyl Lys27 (H3K27me3) in the Bhlhb4 locus were lower in Islet-1-positive BP cells and amacrine cells than in the Islet-1-negative cell fraction. The Islet-1-negative cell fraction consisted mainly of photoreceptors, suggestive of lineage-specific demethylation of H3K27me3 in the Bhlhb4 locus. We propose that lineage-specific H3K27me3 demethylation of critical gene loci by spatiotemporal-specific Jmjd3 expression is required for appropriate maturation of retinal cells.histone methylation | progenitor | interneuron

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“…When bipolar cells are prevented from developing fully, they may undergo apoptosis (Bramblett et al, 2004). To determine whether bipolar cells are prone to apoptosis in Ribeye a-depleted animals, we performed TUNEL assay, which marks DNA fragmentation in cells undergoing apoptosis.…”

Section: Ribeye a Deficiency Causes Apoptosismentioning

confidence: 99%

“…They all lack PKC␣-positive bipolar cells (Burmeister et al, 1996;Ferda Percin et al, 2000;Tomita et al, 2000;Hatakeyama et al, 2001;Bramblett et al, 2004). However, because Ribeye a is excluded from the nucleus, it is the only protein in this group that is not a transcription factor.…”

Section: Math3mentioning

confidence: 99%

TworibeyeGenes in Teleosts: The Role of Ribeye in Ribbon Formation and Bipolar Cell Development

Wan¹,

Almers²,

Chen³

2005

J. Neurosci.

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Ribeye is the only known protein specific to synaptic ribbon, but its function is unclear. We show that the teleost fish, Fugu and zebrafish, have two ribeye genes, ribeye a and ribeye b. Whole-mount in situ hybridization revealed that ribeye a is expressed in tissues containing synaptic ribbons, including the pineal gland, inner ear, and retina. Ribeye b is absent in the pineal gland. In the retina, ribeye a is expressed in both photoreceptors and bipolar cells, whereas ribeye b is detected only in photoreceptors. To study the function of Ribeye a in retina, we depleted it by morpholino antisense oligos. Fish deficient in Ribeye a lack an optokinetic response and have shorter synaptic ribbons in photoreceptors and fewer synaptic ribbons in bipolar cells. Their bipolar cells still target Syntaxin-3 proteins to the inner plexiform layer and have abundant vsx1 mRNA. However, they lack large synaptic terminals and show increased apoptosis. Rod bipolar cells are fewer in number and/or deficient in PKC␣. Recovery of Ribeye a levels rescues the optokinetic response, increases the number of PKC␣-positive bipolar cells, and stops apoptosis. We conclude that Ribeye a is important for late steps in bipolar cell development.

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The Transcription Factor Bhlhb4 Is Required for Rod Bipolar Cell Maturation

Cited by 97 publications

References 42 publications

Direct rod input to cone BCs and direct cone input to rod BCs challenge the traditional view of mammalian BC circuitry

Direct rod input to cone BCs and direct cone input to rod BCs challenge the traditional view of mammalian BC circuitry

Histone demethylase Jmjd3 is required for the development of subsets of retinal bipolar cells

TworibeyeGenes in Teleosts: The Role of Ribeye in Ribbon Formation and Bipolar Cell Development

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