Targeted deletion of an NRL- and CRX-regulated alternative promoter specifically silences FERM and PDZ domain containing 1 (Frmpd1) in rod photoreceptors.
Journal
Human molecular genetics
ISSN: 1460-2083
Titre abrégé: Hum Mol Genet
Pays: England
ID NLM: 9208958
Informations de publication
Date de publication:
01 03 2019
01 03 2019
Historique:
received:
20
09
2018
revised:
15
10
2018
accepted:
07
11
2018
pubmed:
18
11
2018
medline:
12
3
2020
entrez:
17
11
2018
Statut:
ppublish
Résumé
Regulation of cell type-specific gene expression is critical for generating neuronal diversity. Transcriptome analyses have unraveled extensive heterogeneity of transcribed sequences in retinal photoreceptors because of alternate splicing and/or promoter usage. Here we show that Frmpd1 (FERM and PDZ domain containing 1) is transcribed from an alternative promoter specifically in the retina. Electroporation of Frmpd1 promoter region, -505 to +382 bp, activated reporter gene expression in mouse retina in vivo. A proximal promoter sequence (-8 to +33 bp) of Frmpd1 binds to neural retina leucine zipper (NRL) and cone-rod homeobox protein (CRX), two rod-specific differentiation factors, and is necessary for activating reporter gene expression in vitro and in vivo. Clustered regularly interspaced short palindromic repeats/Cas9-mediated deletion of the genomic region, including NRL and CRX binding sites, in vivo completely eliminated Frmpd1 expression in rods and dramatically reduced expression in rod bipolar cells, thereby overcoming embryonic lethality caused by germline Frmpd1 deletion. Our studies demonstrate that a cell type-specific regulatory control region is a credible target for creating loss-of-function alleles of widely expressed genes.
Identifiants
pubmed: 30445545
pii: 5184335
doi: 10.1093/hmg/ddy388
pmc: PMC6381315
doi:
Substances chimiques
Carrier Proteins
0
Frmpd1 protein, human
0
Types de publication
Journal Article
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
804-817Subventions
Organisme : Intramural NIH HHS
ID : Z01 EY000450
Pays : United States
Informations de copyright
Published by Oxford University Press 2018.
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