Abstract
Potocki-Lupski syndrome (PTLS) is a genomic disorder associated with an ∼3 Mb duplication in 17p11.2. Clinical features include leanness, intellectual disability, autistic features and developmental deficits. RAI1 gene dosage is associated with the PTLS phenotypes. To understand where and when Rai1 overexpression is detrimental, we generated a mouse that over-expresses Rai1 conditionally in forebrain neurons (I-Rai1). Phenotypic characterization of I-Rai1 mice showed significant underweight, hyperactivity and impaired learning and memory ability compared with wild-type littermates. Doxycycline administration can turn off the transgene expression allowing the restoration of Rai1 normal expression levels. When the transgene was turned off from conception to 3 months of age, no phenotypic differences were observed between I-Rai1 and their wild-type littermates. Surprisingly, we found that turning off the transgene expression before the onset of the phenotypes (1-3 months) or after the onset of the phenotypes (3-5 months) cannot prevent nor reverse the phenotypic outcomes. Our results indicate that Rai1 dosage in forebrain neurons is critical during the development and is related to body weight regulation, activity levels and learning and memory.
| Original language | English |
|---|---|
| Pages (from-to) | 1771-1782 |
| Number of pages | 12 |
| Journal | Human Molecular Genetics |
| Volume | 23 |
| Issue number | 7 |
| DOIs | |
| State | Published - Apr 1 2014 |
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ASJC Scopus subject areas
- Medicine(all)
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Correct developmental expression level of Rai1 in forebrain neurons is required for control of body weight, activity levels and learning and memory. / Cao, Lei; Molina, Jessica; Abad, Clemer; Carmona-Mora, Paulina; Cárdenas Oyarzo, Areli; Young, Juan; Walz, Katherina.
In: Human Molecular Genetics, Vol. 23, No. 7, 01.04.2014, p. 1771-1782.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Correct developmental expression level of Rai1 in forebrain neurons is required for control of body weight, activity levels and learning and memory
AU - Cao, Lei
AU - Molina, Jessica
AU - Abad, Clemer
AU - Carmona-Mora, Paulina
AU - Cárdenas Oyarzo, Areli
AU - Young, Juan
AU - Walz, Katherina
PY - 2014/4/1
Y1 - 2014/4/1
N2 - Potocki-Lupski syndrome (PTLS) is a genomic disorder associated with an ∼3 Mb duplication in 17p11.2. Clinical features include leanness, intellectual disability, autistic features and developmental deficits. RAI1 gene dosage is associated with the PTLS phenotypes. To understand where and when Rai1 overexpression is detrimental, we generated a mouse that over-expresses Rai1 conditionally in forebrain neurons (I-Rai1). Phenotypic characterization of I-Rai1 mice showed significant underweight, hyperactivity and impaired learning and memory ability compared with wild-type littermates. Doxycycline administration can turn off the transgene expression allowing the restoration of Rai1 normal expression levels. When the transgene was turned off from conception to 3 months of age, no phenotypic differences were observed between I-Rai1 and their wild-type littermates. Surprisingly, we found that turning off the transgene expression before the onset of the phenotypes (1-3 months) or after the onset of the phenotypes (3-5 months) cannot prevent nor reverse the phenotypic outcomes. Our results indicate that Rai1 dosage in forebrain neurons is critical during the development and is related to body weight regulation, activity levels and learning and memory.
AB - Potocki-Lupski syndrome (PTLS) is a genomic disorder associated with an ∼3 Mb duplication in 17p11.2. Clinical features include leanness, intellectual disability, autistic features and developmental deficits. RAI1 gene dosage is associated with the PTLS phenotypes. To understand where and when Rai1 overexpression is detrimental, we generated a mouse that over-expresses Rai1 conditionally in forebrain neurons (I-Rai1). Phenotypic characterization of I-Rai1 mice showed significant underweight, hyperactivity and impaired learning and memory ability compared with wild-type littermates. Doxycycline administration can turn off the transgene expression allowing the restoration of Rai1 normal expression levels. When the transgene was turned off from conception to 3 months of age, no phenotypic differences were observed between I-Rai1 and their wild-type littermates. Surprisingly, we found that turning off the transgene expression before the onset of the phenotypes (1-3 months) or after the onset of the phenotypes (3-5 months) cannot prevent nor reverse the phenotypic outcomes. Our results indicate that Rai1 dosage in forebrain neurons is critical during the development and is related to body weight regulation, activity levels and learning and memory.
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U2 - 10.1093/hmg/ddt568
DO - 10.1093/hmg/ddt568
M3 - Article
VL - 23
SP - 1771
EP - 1782
JO - Human Molecular Genetics
JF - Human Molecular Genetics
SN - 0964-6906
IS - 7
ER -