Haploinsufficiency of intraflagellar transport protein 172 causes autism-like behavioral phenotypes in mice through BDNF
Introduction: Primary cilia are hair-like solitary organelles growing on most mammalian cells that play fundamental roles in embryonic patterning and organogenesis. Defective cilia often cause a suite of inherited diseases called ciliopathies with multifaceted manifestations. Intraflagellar transpor...
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Elsevier
2025-07-01
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| author | Nanxi Zheng Shilin Luo Xin Zhang Ling Hu Muzhi Huang Mingyu Li Colin McCaig Yu-Qiang Ding Bing Lang |
| author_facet | Nanxi Zheng Shilin Luo Xin Zhang Ling Hu Muzhi Huang Mingyu Li Colin McCaig Yu-Qiang Ding Bing Lang |
| author_sort | Nanxi Zheng |
| collection | DOAJ |
| description | Introduction: Primary cilia are hair-like solitary organelles growing on most mammalian cells that play fundamental roles in embryonic patterning and organogenesis. Defective cilia often cause a suite of inherited diseases called ciliopathies with multifaceted manifestations. Intraflagellar transport (IFT), a bidirectional protein trafficking along the cilium, actively facilitates the formation and absorption of primary cilia. IFT172 is the largest component of the IFT-B complex, and its roles in Bardet-Biedl Syndrome (BBS) have been appreciated with unclear mechanisms. Objectives: We performed a battery of behavioral tests with Ift172 haploinsufficiency (Ift172+/-) and WT littermates. We use RNA sequencing to identify the genes and signaling pathways that are differentially expressed and enriched in the hippocampus of Ift172+/- mice. Using AAV-mediated sparse labeling, electron microscopic examination, patch clamp and local field potential recording, western blot, luciferase reporter assay, chromatin immunoprecipitation, and neuropharmacological approach, we investigated the underlying mechanisms for the aberrant phenotypes presented by Ift172+/- mice. Results: Ift172+/- mice displayed excessive self-grooming, elevated anxiety, and impaired cognition. RNA sequencing revealed enrichment of differentially expressed genes in pathways relevant to axonogenesis and synaptic plasticity, which were further confirmed by less spine density and synaptic number. Ift172+/- mice demonstrated fewer parvalbumin-expressing neurons, decreased inhibitory synaptic transmission, augmented theta oscillation, and sharp-wave ripples in the CA1 region. Moreover, Ift172 haploinsufficiency caused less BDNF production and less activated BDNF-TrkB signaling pathway through transcription factor Gli3. Application of 7,8-Dihydroxyflavone, a potent small molecular TrkB agonist, fully restored BDNF-TrkB signaling activity and abnormal behavioral phenotypes presented by Ift172+/- mice. With luciferase and chip assays, we provided further evidence that Gli3 may physically interact with BDNF promoter I and regulate BDNF expression. Conclusions: Our data suggest that Ift172 per se drives neurotrophic effects and, when defective, could cause neurodevelopmental disorders reminiscent of autism-like disorders. |
| format | Article |
| id | doaj-art-73c663e3168d4b41a16e89cd7e5df3da |
| institution | DOAJ |
| issn | 2090-1232 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Elsevier |
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| series | Journal of Advanced Research |
| spelling | doaj-art-73c663e3168d4b41a16e89cd7e5df3da2025-08-20T03:22:50ZengElsevierJournal of Advanced Research2090-12322025-07-017368169510.1016/j.jare.2024.08.041Haploinsufficiency of intraflagellar transport protein 172 causes autism-like behavioral phenotypes in mice through BDNFNanxi Zheng0Shilin Luo1Xin Zhang2Ling Hu3Muzhi Huang4Mingyu Li5Colin McCaig6Yu-Qiang Ding7Bing Lang8Department of Psychiatry, National Clinical Research Center for Mental Disorders and National Center for Mental Disorders, The Second Xiangya Hospital, Central South University, Changsha 410011, China; Department of Psychiatry, Fujian Medical University Affiliated Fuzhou Neuropsychiatric Hospital, Fuzhou 350005, ChinaDepartment of Neurology, Xiangya Hospital of Central South University, Changsha 410008, China; National Clinical Research Center for Geriatric Disorder, Central South University, Changsha, China; Engineering Research Center of Human Province in Cognitive Impairment Disorders, Changsha 410008, ChinaCollege of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou 310014, ChinaState Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, 200433 Shanghai, ChinaDepartment of Psychiatry, National Clinical Research Center for Mental Disorders and National Center for Mental Disorders, The Second Xiangya Hospital, Central South University, Changsha 410011, ChinaDepartment of Psychiatry, National Clinical Research Center for Mental Disorders and National Center for Mental Disorders, The Second Xiangya Hospital, Central South University, Changsha 410011, ChinaSchool of Medicine, Medical Sciences & Nutrition, Institute of Medical Sciences, University of Aberdeen, Foresterhill, AB25 2ZD Aberdeen, Scotland, UKState Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, 200433 Shanghai, ChinaDepartment of Psychiatry, National Clinical Research Center for Mental Disorders and National Center for Mental Disorders, The Second Xiangya Hospital, Central South University, Changsha 410011, China; Corresponding author.Introduction: Primary cilia are hair-like solitary organelles growing on most mammalian cells that play fundamental roles in embryonic patterning and organogenesis. Defective cilia often cause a suite of inherited diseases called ciliopathies with multifaceted manifestations. Intraflagellar transport (IFT), a bidirectional protein trafficking along the cilium, actively facilitates the formation and absorption of primary cilia. IFT172 is the largest component of the IFT-B complex, and its roles in Bardet-Biedl Syndrome (BBS) have been appreciated with unclear mechanisms. Objectives: We performed a battery of behavioral tests with Ift172 haploinsufficiency (Ift172+/-) and WT littermates. We use RNA sequencing to identify the genes and signaling pathways that are differentially expressed and enriched in the hippocampus of Ift172+/- mice. Using AAV-mediated sparse labeling, electron microscopic examination, patch clamp and local field potential recording, western blot, luciferase reporter assay, chromatin immunoprecipitation, and neuropharmacological approach, we investigated the underlying mechanisms for the aberrant phenotypes presented by Ift172+/- mice. Results: Ift172+/- mice displayed excessive self-grooming, elevated anxiety, and impaired cognition. RNA sequencing revealed enrichment of differentially expressed genes in pathways relevant to axonogenesis and synaptic plasticity, which were further confirmed by less spine density and synaptic number. Ift172+/- mice demonstrated fewer parvalbumin-expressing neurons, decreased inhibitory synaptic transmission, augmented theta oscillation, and sharp-wave ripples in the CA1 region. Moreover, Ift172 haploinsufficiency caused less BDNF production and less activated BDNF-TrkB signaling pathway through transcription factor Gli3. Application of 7,8-Dihydroxyflavone, a potent small molecular TrkB agonist, fully restored BDNF-TrkB signaling activity and abnormal behavioral phenotypes presented by Ift172+/- mice. With luciferase and chip assays, we provided further evidence that Gli3 may physically interact with BDNF promoter I and regulate BDNF expression. Conclusions: Our data suggest that Ift172 per se drives neurotrophic effects and, when defective, could cause neurodevelopmental disorders reminiscent of autism-like disorders.http://www.sciencedirect.com/science/article/pii/S2090123224003825Intraflagellar transport protein 172Primary ciliaAutism spectrum disordersSonic HedgehogBDNFBardet Biedl Syndrome |
| spellingShingle | Nanxi Zheng Shilin Luo Xin Zhang Ling Hu Muzhi Huang Mingyu Li Colin McCaig Yu-Qiang Ding Bing Lang Haploinsufficiency of intraflagellar transport protein 172 causes autism-like behavioral phenotypes in mice through BDNF Journal of Advanced Research Intraflagellar transport protein 172 Primary cilia Autism spectrum disorders Sonic Hedgehog BDNF Bardet Biedl Syndrome |
| title | Haploinsufficiency of intraflagellar transport protein 172 causes autism-like behavioral phenotypes in mice through BDNF |
| title_full | Haploinsufficiency of intraflagellar transport protein 172 causes autism-like behavioral phenotypes in mice through BDNF |
| title_fullStr | Haploinsufficiency of intraflagellar transport protein 172 causes autism-like behavioral phenotypes in mice through BDNF |
| title_full_unstemmed | Haploinsufficiency of intraflagellar transport protein 172 causes autism-like behavioral phenotypes in mice through BDNF |
| title_short | Haploinsufficiency of intraflagellar transport protein 172 causes autism-like behavioral phenotypes in mice through BDNF |
| title_sort | haploinsufficiency of intraflagellar transport protein 172 causes autism like behavioral phenotypes in mice through bdnf |
| topic | Intraflagellar transport protein 172 Primary cilia Autism spectrum disorders Sonic Hedgehog BDNF Bardet Biedl Syndrome |
| url | http://www.sciencedirect.com/science/article/pii/S2090123224003825 |
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