Dataset Information

Progenitor division and cell autonomous neurosecretion are required for rod photoreceptor sublaminar positioning.

ABSTRACT: Migration is essential for the laminar stratification and connectivity of neurons in the central nervous system. In the retina, photoreceptors (PRs) migrate to positions according to birthdate, with early-born cells localizing to the basal-most side of the outer nuclear layer. It was proposed that apical progenitor mitoses physically drive these basal translocations non-cell autonomously, but direct evidence is lacking, and whether other mechanisms participate is unknown. Here, combining loss- or gain-of-function assays to manipulate cell cycle regulators (Sonic hedgehog, Cdkn1a/p21) with an in vivo lentiviral labelling strategy, we demonstrate that progenitor division is one of two forces driving basal translocation of rod soma. Indeed, replacing Shh activity rescues abnormal rod translocation in retinal explants. Unexpectedly, we show that rod differentiation also promotes rod soma translocation. While outer segment function or formation is dispensable, Crx and SNARE-dependent synaptic function are essential. Thus, both non-cell and cell autonomous mechanisms underpin PR soma sublaminar positioning in the mammalian retina.

SUBMITTER: Gurdita A

PROVIDER: S-EPMC10589646 | biostudies-literature | 2023 Oct

REPOSITORIES: biostudies-literature

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Publications

Progenitor division and cell autonomous neurosecretion are required for rod photoreceptor sublaminar positioning.

Gurdita Akshay A Pham Truong Victor Q B VQB Dolati Parnian P Juric Matey M Tachibana Nobuhiko N Liu Zhongda C ZC Ortín-Martínez Arturo A Ibrahimi Mostafa M Pokrajac Nenad T NT Comanita Lacrimioara L Pacal Marek M Huang Mengjia M Sugita Shuzo S Bremner Rod R Wallace Valerie A VA

Proceedings of the National Academy of Sciences of the United States of America 20231009 42

Migration is essential for the laminar stratification and connectivity of neurons in the central nervous system. In the retina, photoreceptors (PRs) migrate to positions according to birthdate, with early-born cells localizing to the basal-most side of the outer nuclear layer. It was proposed that apical progenitor mitoses physically drive these basal translocations non-cell autonomously, but direct evidence is lacking, and whether other mechanisms participate is unknown. Here, combining loss- o ...[more]

PMID: 37812728

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Project description:Functional vision restoration is within reach via stem cell therapy, but one of the largest obstacles is the derivation of colour-sensitive cone photoreceptors that are required for high-acuity daytime vision. To enhance progress made using nocturnal murine models, we instead utilize cone-rich zebrafish and herein investigate relationships between gdf6a and tbx2b in cone photoreceptor development. Growth/differentiation factor 6a (gdf6a), a bone morphogenetic protein family ligand, is an emerging factor in photoreceptor degenerative diseases. The T-box transcription factor tbx2b is required to specify UV cone photoreceptor fate instead of rod photoreceptor fate. Interactions between these factors in cone development would be unanticipated, considering the discrete phenotypes in their respective mutants. However, gdf6a positively modulates the abundance of tbx2b transcript during early eye morphogenesis, and we extended this conclusion to later stages of retinal development comprising the times when photoreceptors differentiate. Despite this, gdf6a-/- larvae possess a normal relative number of UV cones and instead present with a low abundance of blue cone photoreceptors, approximately half that of siblings (p<0.001), supporting a differential role for gdf6a amongst the spectral subtypes of cone photoreceptors. Further, gdf6a-/- larvae from breeding of compound heterozygous gdf6a+/-;tbx2b+/- mutants exhibit the recessive lots-of-rods phenotype (which also shows a paucity of UV cones) at significantly elevated rates (44% or 48% for each of two tbx2b alleles, χ2 p≤0.007 for each compared to expected Mendelian 25%). Thus the gdf6a-/- background sensitizes fish such that the recessive lots-of-rods phenotype can appear in heterozygous tbx2b+/- fish. Overall, this work establishes a novel link between tbx2b and gdf6a in determining photoreceptor fates, defining the nexus of an intricate pathway influencing the abundance of cone spectral subtypes and specifying rod vs. cone photoreceptors. Understanding this interaction is a necessary step in the refinement of stem cell-based restoration of daytime vision in humans.

Dataset Information

Progenitor division and cell autonomous neurosecretion are required for rod photoreceptor sublaminar positioning.

Publications

Progenitor division and cell autonomous neurosecretion are required for rod photoreceptor sublaminar positioning.

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