A Truncating Mutation of Alms1 Reduces the Number of Hypothalamic Neuronal Cilia in Obese Mice

Deborah HEYDET, Lesley X. Chen, Claire Larter, Chrystal Inglis, Michael A. Silverman, Geoffrey C. Farrell, Michel R. Leroux

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

Primary cilia are ubiquitous cellular antennae whose dysfunction collectively causes various disorders, including vision and hearing impairment, as well as renal, skeletal, and central nervous system anomalies. One ciliopathy, Alström syndrome, is closely related to Bardet–Biedl syndrome (BBS), sharing amongst other phenotypic features morbid obesity. As the cellular and molecular links between weight regulation and cilia are poorly understood, we used the obese mouse strain foz/foz, bearing a truncating mutation in the Alström syndrome protein (Alms1), to help elucidate why it develops hyperphagia, leading to early onset obesity and metabolic anomalies. Our in vivo studies reveal that Alms1 localizes at the base of cilia in hypothalamic neurons, which are implicated in the control of satiety. Alms1 is lost from this location in foz/foz mice, coinciding with a strong postnatal reduction (∼70%) in neurons displaying cilia marked with adenylyl cyclase 3 (AC3), a signaling protein implicated in obesity. Notably, the reduction in AC3‐bearing cilia parallels the decrease in cilia containing two appetite‐regulating proteins, Mchr1 and Sstr3, as well as another established Arl13b ciliary marker, consistent with progressive loss of cilia during development. Together, our results suggest that Alms1 maintains the function of neuronal cilia implicated in weight regulation by influencing the maintenance and/or stability of the organelle. Given that Mchr1 and Sstr3 localization to remaining cilia is maintained in foz/foz animals but known to be lost from BBS knockout mice, our findings suggest different molecular etiologies for the satiety defects associated with the Alström syndrome and BBS ciliopathies
Original languageEnglish
Pages (from-to)1-13
Number of pages13
JournalDevelopmental Neurobiology
Volume73
Issue number1
DOIs
Publication statusPublished - 2013
Externally publishedYes

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Obese Mice
Cilia
Mutation
Obesity
Nervous System Malformations
Neurons
Weights and Measures
Hyperphagia
Proteins
Morbid Obesity
Vision Disorders
Hearing Loss
Adenylyl Cyclases
Knockout Mice
Organelles
Central Nervous System
Maintenance
Kidney

Cite this

HEYDET, D., Chen, L. X., Larter, C., Inglis, C., Silverman, M. A., Farrell, G. C., & Leroux, M. R. (2013). A Truncating Mutation of Alms1 Reduces the Number of Hypothalamic Neuronal Cilia in Obese Mice. Developmental Neurobiology, 73(1), 1-13. https://doi.org/10.1002/dneu.22031
HEYDET, Deborah ; Chen, Lesley X. ; Larter, Claire ; Inglis, Chrystal ; Silverman, Michael A. ; Farrell, Geoffrey C. ; Leroux, Michel R. / A Truncating Mutation of Alms1 Reduces the Number of Hypothalamic Neuronal Cilia in Obese Mice. In: Developmental Neurobiology. 2013 ; Vol. 73, No. 1. pp. 1-13.
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abstract = "Primary cilia are ubiquitous cellular antennae whose dysfunction collectively causes various disorders, including vision and hearing impairment, as well as renal, skeletal, and central nervous system anomalies. One ciliopathy, Alstr{\"o}m syndrome, is closely related to Bardet–Biedl syndrome (BBS), sharing amongst other phenotypic features morbid obesity. As the cellular and molecular links between weight regulation and cilia are poorly understood, we used the obese mouse strain foz/foz, bearing a truncating mutation in the Alstr{\"o}m syndrome protein (Alms1), to help elucidate why it develops hyperphagia, leading to early onset obesity and metabolic anomalies. Our in vivo studies reveal that Alms1 localizes at the base of cilia in hypothalamic neurons, which are implicated in the control of satiety. Alms1 is lost from this location in foz/foz mice, coinciding with a strong postnatal reduction (∼70{\%}) in neurons displaying cilia marked with adenylyl cyclase 3 (AC3), a signaling protein implicated in obesity. Notably, the reduction in AC3‐bearing cilia parallels the decrease in cilia containing two appetite‐regulating proteins, Mchr1 and Sstr3, as well as another established Arl13b ciliary marker, consistent with progressive loss of cilia during development. Together, our results suggest that Alms1 maintains the function of neuronal cilia implicated in weight regulation by influencing the maintenance and/or stability of the organelle. Given that Mchr1 and Sstr3 localization to remaining cilia is maintained in foz/foz animals but known to be lost from BBS knockout mice, our findings suggest different molecular etiologies for the satiety defects associated with the Alstr{\"o}m syndrome and BBS ciliopathies",
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HEYDET, D, Chen, LX, Larter, C, Inglis, C, Silverman, MA, Farrell, GC & Leroux, MR 2013, 'A Truncating Mutation of Alms1 Reduces the Number of Hypothalamic Neuronal Cilia in Obese Mice', Developmental Neurobiology, vol. 73, no. 1, pp. 1-13. https://doi.org/10.1002/dneu.22031

A Truncating Mutation of Alms1 Reduces the Number of Hypothalamic Neuronal Cilia in Obese Mice. / HEYDET, Deborah; Chen, Lesley X.; Larter, Claire; Inglis, Chrystal; Silverman, Michael A.; Farrell, Geoffrey C.; Leroux, Michel R.

In: Developmental Neurobiology, Vol. 73, No. 1, 2013, p. 1-13.

Research output: Contribution to journalArticle

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T1 - A Truncating Mutation of Alms1 Reduces the Number of Hypothalamic Neuronal Cilia in Obese Mice

AU - HEYDET, Deborah

AU - Chen, Lesley X.

AU - Larter, Claire

AU - Inglis, Chrystal

AU - Silverman, Michael A.

AU - Farrell, Geoffrey C.

AU - Leroux, Michel R.

PY - 2013

Y1 - 2013

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AB - Primary cilia are ubiquitous cellular antennae whose dysfunction collectively causes various disorders, including vision and hearing impairment, as well as renal, skeletal, and central nervous system anomalies. One ciliopathy, Alström syndrome, is closely related to Bardet–Biedl syndrome (BBS), sharing amongst other phenotypic features morbid obesity. As the cellular and molecular links between weight regulation and cilia are poorly understood, we used the obese mouse strain foz/foz, bearing a truncating mutation in the Alström syndrome protein (Alms1), to help elucidate why it develops hyperphagia, leading to early onset obesity and metabolic anomalies. Our in vivo studies reveal that Alms1 localizes at the base of cilia in hypothalamic neurons, which are implicated in the control of satiety. Alms1 is lost from this location in foz/foz mice, coinciding with a strong postnatal reduction (∼70%) in neurons displaying cilia marked with adenylyl cyclase 3 (AC3), a signaling protein implicated in obesity. Notably, the reduction in AC3‐bearing cilia parallels the decrease in cilia containing two appetite‐regulating proteins, Mchr1 and Sstr3, as well as another established Arl13b ciliary marker, consistent with progressive loss of cilia during development. Together, our results suggest that Alms1 maintains the function of neuronal cilia implicated in weight regulation by influencing the maintenance and/or stability of the organelle. Given that Mchr1 and Sstr3 localization to remaining cilia is maintained in foz/foz animals but known to be lost from BBS knockout mice, our findings suggest different molecular etiologies for the satiety defects associated with the Alström syndrome and BBS ciliopathies

KW - Primary Cilium

KW - Hypothalamus

KW - Obesity

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