TLX3 regulates CGN progenitor proliferation during cerebellum development and its dysfunction can lead to autism
Summary: Tlx3, a master regulator of the fate specification of excitatory neurons, is primarily known to function in post-mitotic cells. Although we have previously identified TLX3 expression in the proliferating granule neuron progenitors (GNPs) of cerebellum, its primary role is unknown. Here, we...
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Elsevier
2024-12-01
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589004224024854 |
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| author | Surendran Parvathy Budhaditya Basu Suresh Surya Rahul Jose Vadakkath Meera Paul Ann Riya Nair Pradeep Jyothi Rajendran Sanalkumar Viviane Praz Nicolò Riggi Biju Surendran Nair Kamalesh K. Gulia Mukesh Kumar Balachandran Krishnamma Binukumar Jackson James |
| author_facet | Surendran Parvathy Budhaditya Basu Suresh Surya Rahul Jose Vadakkath Meera Paul Ann Riya Nair Pradeep Jyothi Rajendran Sanalkumar Viviane Praz Nicolò Riggi Biju Surendran Nair Kamalesh K. Gulia Mukesh Kumar Balachandran Krishnamma Binukumar Jackson James |
| author_sort | Surendran Parvathy |
| collection | DOAJ |
| description | Summary: Tlx3, a master regulator of the fate specification of excitatory neurons, is primarily known to function in post-mitotic cells. Although we have previously identified TLX3 expression in the proliferating granule neuron progenitors (GNPs) of cerebellum, its primary role is unknown. Here, we demonstrate that the dysfunction of Tlx3 from the GNPs significantly reduced its proliferation through regulating anti-proliferative genes. Consequently, the altered generation of GNPs resulted in cerebellar hypoplasia, patterning defects, granule neuron-Purkinje ratio imbalance, and aberrant synaptic connections in the cerebellum. This altered cerebellar homeostasis manifested into a typical autism-like behavior in mice with motor, and social function disabilities. We also show the presence of TLX3 variants with uncharacterized mutations in human cases of autism spectrum disorder (ASD). Altogether, our study establishes Tlx3 as a critical gene involved in developing GNPs and that its deletion from the early developmental stage culminates in autism. |
| format | Article |
| id | doaj-art-aecadb74d7004793bc3b59c2ed742ca8 |
| institution | DOAJ |
| issn | 2589-0042 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj-art-aecadb74d7004793bc3b59c2ed742ca82025-08-20T02:39:48ZengElsevieriScience2589-00422024-12-01271211126010.1016/j.isci.2024.111260TLX3 regulates CGN progenitor proliferation during cerebellum development and its dysfunction can lead to autismSurendran Parvathy0Budhaditya Basu1Suresh Surya2Rahul Jose3Vadakkath Meera4Paul Ann Riya5Nair Pradeep Jyothi6Rajendran Sanalkumar7Viviane Praz8Nicolò Riggi9Biju Surendran Nair10Kamalesh K. Gulia11Mukesh Kumar12Balachandran Krishnamma Binukumar13Jackson James14Neuro Stem Cell Biology Laboratory, Neurobiology Division, Rajiv Gandhi Centre for Biotechnology (BRIC-RGCB), Thiruvananthapuram, Kerala 695 014, India; Research Centre, The University of Kerala, Thiruvananthapuram, Kerala 695 014, IndiaNeuro Stem Cell Biology Laboratory, Neurobiology Division, Rajiv Gandhi Centre for Biotechnology (BRIC-RGCB), Thiruvananthapuram, Kerala 695 014, India; Regional Centre for Biotechnology (BRIC-RCB), Faridabad, Haryana 121001, IndiaNeuro Stem Cell Biology Laboratory, Neurobiology Division, Rajiv Gandhi Centre for Biotechnology (BRIC-RGCB), Thiruvananthapuram, Kerala 695 014, India; Research Centre, The University of Kerala, Thiruvananthapuram, Kerala 695 014, IndiaNeuro Stem Cell Biology Laboratory, Neurobiology Division, Rajiv Gandhi Centre for Biotechnology (BRIC-RGCB), Thiruvananthapuram, Kerala 695 014, India; Regional Centre for Biotechnology (BRIC-RCB), Faridabad, Haryana 121001, IndiaNeuro Stem Cell Biology Laboratory, Neurobiology Division, Rajiv Gandhi Centre for Biotechnology (BRIC-RGCB), Thiruvananthapuram, Kerala 695 014, India; Research Centre, The University of Kerala, Thiruvananthapuram, Kerala 695 014, IndiaNeuro Stem Cell Biology Laboratory, Neurobiology Division, Rajiv Gandhi Centre for Biotechnology (BRIC-RGCB), Thiruvananthapuram, Kerala 695 014, India; Research Centre, The University of Kerala, Thiruvananthapuram, Kerala 695 014, IndiaNeuro Stem Cell Biology Laboratory, Neurobiology Division, Rajiv Gandhi Centre for Biotechnology (BRIC-RGCB), Thiruvananthapuram, Kerala 695 014, India; Research Centre, The University of Kerala, Thiruvananthapuram, Kerala 695 014, IndiaCHUV-Lausanne University Hospital, Rue du Bugnon 46, 1005 Lausanne, SwitzerlandCHUV-Lausanne University Hospital, Rue du Bugnon 46, 1005 Lausanne, SwitzerlandCHUV-Lausanne University Hospital, Rue du Bugnon 46, 1005 Lausanne, SwitzerlandNeuro Stem Cell Biology Laboratory, Neurobiology Division, Rajiv Gandhi Centre for Biotechnology (BRIC-RGCB), Thiruvananthapuram, Kerala 695 014, IndiaDivision of Sleep Research, Department of Applied Biology, Biomedical Technology Wing, Sree Chitra Tirunal Institute for Medical Sciences and Technology (SCTIMST), Trivandrum, Kerala 695012, IndiaInstitute of Genomics and Integrative Biology (CSIR-IGIB), New Delhi 110025, IndiaInstitute of Genomics and Integrative Biology (CSIR-IGIB), New Delhi 110025, IndiaNeuro Stem Cell Biology Laboratory, Neurobiology Division, Rajiv Gandhi Centre for Biotechnology (BRIC-RGCB), Thiruvananthapuram, Kerala 695 014, India; Research Centre, The University of Kerala, Thiruvananthapuram, Kerala 695 014, India; Regional Centre for Biotechnology (BRIC-RCB), Faridabad, Haryana 121001, India; Corresponding authorSummary: Tlx3, a master regulator of the fate specification of excitatory neurons, is primarily known to function in post-mitotic cells. Although we have previously identified TLX3 expression in the proliferating granule neuron progenitors (GNPs) of cerebellum, its primary role is unknown. Here, we demonstrate that the dysfunction of Tlx3 from the GNPs significantly reduced its proliferation through regulating anti-proliferative genes. Consequently, the altered generation of GNPs resulted in cerebellar hypoplasia, patterning defects, granule neuron-Purkinje ratio imbalance, and aberrant synaptic connections in the cerebellum. This altered cerebellar homeostasis manifested into a typical autism-like behavior in mice with motor, and social function disabilities. We also show the presence of TLX3 variants with uncharacterized mutations in human cases of autism spectrum disorder (ASD). Altogether, our study establishes Tlx3 as a critical gene involved in developing GNPs and that its deletion from the early developmental stage culminates in autism.http://www.sciencedirect.com/science/article/pii/S2589004224024854NeuroscienceMolecular NeuroscienceCellular NeuroscienceOmicsTranscriptomics |
| spellingShingle | Surendran Parvathy Budhaditya Basu Suresh Surya Rahul Jose Vadakkath Meera Paul Ann Riya Nair Pradeep Jyothi Rajendran Sanalkumar Viviane Praz Nicolò Riggi Biju Surendran Nair Kamalesh K. Gulia Mukesh Kumar Balachandran Krishnamma Binukumar Jackson James TLX3 regulates CGN progenitor proliferation during cerebellum development and its dysfunction can lead to autism iScience Neuroscience Molecular Neuroscience Cellular Neuroscience Omics Transcriptomics |
| title | TLX3 regulates CGN progenitor proliferation during cerebellum development and its dysfunction can lead to autism |
| title_full | TLX3 regulates CGN progenitor proliferation during cerebellum development and its dysfunction can lead to autism |
| title_fullStr | TLX3 regulates CGN progenitor proliferation during cerebellum development and its dysfunction can lead to autism |
| title_full_unstemmed | TLX3 regulates CGN progenitor proliferation during cerebellum development and its dysfunction can lead to autism |
| title_short | TLX3 regulates CGN progenitor proliferation during cerebellum development and its dysfunction can lead to autism |
| title_sort | tlx3 regulates cgn progenitor proliferation during cerebellum development and its dysfunction can lead to autism |
| topic | Neuroscience Molecular Neuroscience Cellular Neuroscience Omics Transcriptomics |
| url | http://www.sciencedirect.com/science/article/pii/S2589004224024854 |
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