NeuroD1 is required for survival of photoreceptors but not pinealocytes: results from targeted gene deletion studies.
NeuroD1 encodes a basic helix-loop-helix transcription factor involved in the development of neural and endocrine structures, including the retina and pineal gland. To determine the effect of NeuroD1 knockout in these tissues, a Cre/loxP recombination strategy was used to target a NeuroD1 floxed gene and generate NeuroD1 conditional knockout (cKO) mice. Tissue specificity was conferred using Cre recombinase expressed under the control of the promoter of Crx, which is selectively expressed in the pineal gland and retina. At 2 months of age, NeuroD1 cKO retinas have a dramatic reduction in rod- and cone-driven electroretinograms and contain shortened and disorganized outer segments; by 4 months, NeuroD1 cKO retinas are devoid of photoreceptors. In contrast, the NeuroD1 cKO pineal gland appears histologically normal. Microarray analysis of 2-month-old NeuroD1 cKO retina and pineal gland identified a subset of genes that were affected 2-100-fold; in addition, a small group of genes exhibit altered differential night/day expression. Included in the down-regulated genes are Aipl1, which is necessary to prevent retinal degeneration, and Ankrd33, whose protein product is selectively expressed in the outer segments. These findings suggest that NeuroD1 may act through Aipl1 and other genes to maintain photoreceptor homeostasis.
Section on Neuroendocrinology, Program in Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.
Margaret J
MJ
Ochocinska
Estela M
EM
Muñoz
Shobi
S
Veleri
Joan L
JL
Weller
Steven L
SL
Coon
Nikita
N
Pozdeyev
P Michael
PM
Iuvone
Sandra
S
Goebbels
Takahisa
T
Furukawa
David C
DC
Klein
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D001973:Bromodeoxyuridine; D002470:Cell Survival / Q000235:genetics; D004596:Electroretinography; D005786:Gene Expression Regulation / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046228:Microarray Analysis; D046529:Microscopy, Electron, Transmission; D009088:Mucoproteins / Q000172:deficiency / Q000235:genetics; D015513:Oncogene Proteins; D055355:Opsins / Q000235:genetics / Q000378:metabolism; D020419:Photoreceptor Cells, Vertebrate / Q000378:metabolism* / Q000648:ultrastructure; D010870:Pineal Gland / Q000166:cytology / Q000378:metabolism / Q000648:ultrastructure; D012333:RNA, Messenger / Q000378:metabolism; D012160:Retina / Q000166:cytology*; D012162:Retinal Degeneration / Q000473:pathology; D014157:Transcription Factors / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D051792:Basic Helix-Loop-Helix Proteins; D001973:Bromodeoxyuridine; D009088:Mucoproteins; D015513:Oncogene Proteins; D055355:Opsins; D012333:RNA, Messenger; D014157:Transcription Factors; C526445:Agr2 protein, mouse; C498604:Aipl1 protein, mouse; C501008:Neurod1 protein, mouse