A novel type of interplexiform amacrine cell in the mouse retina

AbstractThe mammalian retina contains a complex mixture of different types of neurons. We find that the microRNA miR-216b is preferentially expressed in postmitotic retinal amacrine cells in the mouse retina, and expression of miR-216a/b and miR-217 in the retina depend in part on Ptf1a, a transcription factor required for amacrine cell differentiation. Surprisingly, ectopic expression of miR-216b, or the related miR-216a, can direct the formation of additional amacrine cells in the developing retina. In addition, we observe the loss of bipolar neurons in the retina after miR-216b expression. We identify the mRNA for the transcriptional regulator Foxn3 as a retinal target of miR-216b by Argonaute PAR-CLIP and reporter analysis. Inhibition of Foxn3 in the postnatal developing retina by RNAi also increases the formation of amacrine cells and reduces bipolar cell formation, while overexpression of Foxn3 inhibits amacrine cell formation prior to the expression of Ptf1a. Disruption of Foxn3 by CRISPR in embryonic retinal explants also reduces amacrine cell formation. Co-expression of Foxn3 can partially reverse the effects of ectopic miR-216b on retinal cell type formation. Our results identify Foxn3 as a novel regulator of interneuron formation in the developing retina and suggest that miR-216b likely regulates expression of Foxn3 and other genes in amacrine cells.

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Regulation of retinal amacrine cell generation by miR-216b and Foxn3

Development ◽

10.1242/dev.199484 ◽

2021 ◽

Author(s):

Huanqing Zhang ◽

Pei Zhuang ◽

Ryan M. Welchko ◽

Manhong Dai ◽

Fan Meng ◽

...

Keyword(s):

Transcription Factor ◽

Amacrine Cell ◽

Ectopic Expression ◽

Cell Formation ◽

Complex Mixture ◽

Amacrine Cells ◽

Retinal Cell ◽

Mouse Retina ◽

Different Types ◽

Retinal Explants

The mammalian retina contains a complex mixture of different types of neurons. We find that microRNA miR-216b is preferentially expressed in postmitotic retinal amacrine cells in the mouse retina, and expression of miR-216a/b and miR-217 in retina depend in part on Ptf1a, a transcription factor required for amacrine cell differentiation. Surprisingly, ectopic expression of miR-216b directed the formation of additional amacrine cells and reduced bipolar neurons in the developing retina. We identify the Foxn3 mRNA as a retinal target of miR-216b by Argonaute PAR-CLIP and reporter analysis. Inhibition of Foxn3, a transcription factor, in the postnatal developing retina by RNAi increased the formation of amacrine cells and reduced bipolar cell formation. Foxn3 disruption by CRISPR in embryonic retinal explants also increased amacrine cell formation, while Foxn3 overexpression inhibited amacrine cell formation prior to Ptf1a expression. Co-expression of Foxn3 partially reversed the effects of ectopic miR-216b on retinal cell formation. Our results identify Foxn3 as a novel regulator of interneuron formation in the developing retina and suggest that miR-216b likely regulates Foxn3 and other genes in amacrine cells.

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Computational and Molecular Properties of Starburst Amacrine Cell Synapses Differ With Postsynaptic Cell Type

Frontiers in Cellular Neuroscience ◽

10.3389/fncel.2021.660773 ◽

2021 ◽

Vol 15 ◽

Author(s):

Joseph Pottackal ◽

Joshua H. Singer ◽

Jonathan B. Demb

Keyword(s):

Amacrine Cell ◽

Ganglion Cells ◽

Spatial Scales ◽

Cell Types ◽

Inhibitory Synapses ◽

Mouse Retina ◽

Presynaptic Neuron ◽

Postsynaptic Cell ◽

Low Pass ◽

Starburst Amacrine Cell

A presynaptic neuron can increase its computational capacity by transmitting functionally distinct signals to each of its postsynaptic cell types. To determine whether such computational specialization occurs over fine spatial scales within a neurite arbor, we investigated computation at output synapses of the starburst amacrine cell (SAC), a critical component of the classical direction-selective (DS) circuit in the retina. The SAC is a non-spiking interneuron that co-releases GABA and acetylcholine and forms closely spaced (<5 μm) inhibitory synapses onto two postsynaptic cell types: DS ganglion cells (DSGCs) and neighboring SACs. During dynamic optogenetic stimulation of SACs in mouse retina, whole-cell recordings of inhibitory postsynaptic currents revealed that GABAergic synapses onto DSGCs exhibit stronger low-pass filtering than those onto neighboring SACs. Computational analyses suggest that this filtering difference can be explained primarily by presynaptic properties, rather than those of the postsynaptic cells per se. Consistent with functionally diverse SAC presynapses, blockade of N-type voltage-gated calcium channels abolished GABAergic currents in SACs but only moderately reduced GABAergic and cholinergic currents in DSGCs. These results jointly demonstrate how specialization of synaptic outputs could enhance parallel processing in a compact interneuron over fine spatial scales. Moreover, the distinct transmission kinetics of GABAergic SAC synapses are poised to support the functional diversity of inhibition within DS circuitry.

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The LIM protein complex establishes a retinal circuitry of visual adaptation by regulating Pax6 α-enhancer activity

eLife ◽

10.7554/elife.21303 ◽

2017 ◽

Vol 6 ◽

Cited By ~ 9

Author(s):

Yeha Kim ◽

Soyeon Lim ◽

Taejeong Ha ◽

You-Hyang Song ◽

Young-In Sohn ◽

...

Keyword(s):

Protein Complex ◽

Transforming Growth Factor ◽

Amacrine Cell ◽

Amacrine Cells ◽

Visual Adaptation ◽

Mouse Retina ◽

Visual Responses ◽

Enhancer Activity ◽

Lim Protein ◽

Retinal Circuitry

The visual responses of vertebrates are sensitive to the overall composition of retinal interneurons including amacrine cells, which tune the activity of the retinal circuitry. The expression of Paired-homeobox 6 (PAX6) is regulated by multiple cis-DNA elements including the intronic α-enhancer, which is active in GABAergic amacrine cell subsets. Here, we report that the transforming growth factor ß1-induced transcript 1 protein (Tgfb1i1) interacts with the LIM domain transcription factors Lhx3 and Isl1 to inhibit the α-enhancer in the post-natal mouse retina. Tgfb1i1-/- mice show elevated α-enhancer activity leading to overproduction of Pax6ΔPD isoform that supports the GABAergic amacrine cell fate maintenance. Consequently, the Tgfb1i1-/- mouse retinas show a sustained light response, which becomes more transient in mice with the auto-stimulation-defective Pax6ΔPBS/ΔPBS mutation. Together, we show the antagonistic regulation of the α-enhancer activity by Pax6 and the LIM protein complex is necessary for the establishment of an inner retinal circuitry, which controls visual adaptation.

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