Myt1l haploinsufficiency leads to obesity and multifaceted behavioral alterations in mice

Background The zinc finger domain containing transcription factor Myt1l is tightly associated with neuronal identity and is the only transcription factor known that is both neuron-specific and expressed in all neuronal subtypes. We identified Myt1l as a powerful reprogramming factor that, in combination with the proneural bHLH factor Ascl1, could induce neuronal fate in fibroblasts. Molecularly, we found it to repress many non-neuronal gene programs, explaining its supportive role to induce and safeguard neuronal identity in combination with proneural bHLH transcriptional activators. Moreover, human genetics studies found MYT1L mutations to cause intellectual disability and autism spectrum disorder often coupled with obesity. Methods Here, we generated and characterized Myt1l-deficient mice. A comprehensive, longitudinal behavioral phenotyping approach was applied. Results Myt1l was necessary for survival beyond 24 h but not for overall histological brain organization. Myt1l heterozygous mice became increasingly overweight and exhibited multifaceted behavioral alterations. In mouse pups, Myt1l haploinsufficiency caused mild alterations in early socio-affective communication through ultrasonic vocalizations. In adulthood, Myt1l heterozygous mice displayed hyperactivity due to impaired habituation learning. Motor performance was reduced in Myt1l heterozygous mice despite intact motor learning, possibly due to muscular hypotonia. While anxiety-related behavior was reduced, acoustic startle reactivity was enhanced, in line with higher sensitivity to loud sound. Finally, Myt1l haploinsufficiency had a negative impact on contextual fear memory retrieval, while cued fear memory retrieval appeared to be intact. Limitations In future studies, additional phenotypes might be identified and a detailed characterization of direct reciprocal social interaction behavior might help to reveal effects of Myt1l haploinsufficiency on social behavior in juvenile and adult mice. Conclusions Behavioral alterations in Myt1l haploinsufficient mice recapitulate several clinical phenotypes observed in humans carrying heterozygous MYT1L mutations and thus serve as an informative model of the human MYT1L syndrome. Ausführliche Beschreibung

Gespeichert in:

Autor*in:	Wöhr, Markus [verfasserIn] Fong, Wendy M. Janas, Justyna A. Mall, Moritz Thome, Christian Vangipuram, Madhuri Meng, Lingjun Südhof, Thomas C. Wernig, Marius

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2022

Schlagwörter:	Transcription factor Autism Obesity Social behavior Ultrasonic vocalization

Anmerkung:	© The Author(s) 2022

Übergeordnetes Werk:	Enthalten in: Molecular autism - London : BioMed Central, 2010, 13(2022), 1 vom: 10. Mai
Übergeordnetes Werk:	volume:13 ; year:2022 ; number:1 ; day:10 ; month:05

Links:	Volltext

DOI / URN:	10.1186/s13229-022-00497-3

Katalog-ID:	SPR050699652

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520			\|a Background The zinc finger domain containing transcription factor Myt1l is tightly associated with neuronal identity and is the only transcription factor known that is both neuron-specific and expressed in all neuronal subtypes. We identified Myt1l as a powerful reprogramming factor that, in combination with the proneural bHLH factor Ascl1, could induce neuronal fate in fibroblasts. Molecularly, we found it to repress many non-neuronal gene programs, explaining its supportive role to induce and safeguard neuronal identity in combination with proneural bHLH transcriptional activators. Moreover, human genetics studies found MYT1L mutations to cause intellectual disability and autism spectrum disorder often coupled with obesity. Methods Here, we generated and characterized Myt1l-deficient mice. A comprehensive, longitudinal behavioral phenotyping approach was applied. Results Myt1l was necessary for survival beyond 24 h but not for overall histological brain organization. Myt1l heterozygous mice became increasingly overweight and exhibited multifaceted behavioral alterations. In mouse pups, Myt1l haploinsufficiency caused mild alterations in early socio-affective communication through ultrasonic vocalizations. In adulthood, Myt1l heterozygous mice displayed hyperactivity due to impaired habituation learning. Motor performance was reduced in Myt1l heterozygous mice despite intact motor learning, possibly due to muscular hypotonia. While anxiety-related behavior was reduced, acoustic startle reactivity was enhanced, in line with higher sensitivity to loud sound. Finally, Myt1l haploinsufficiency had a negative impact on contextual fear memory retrieval, while cued fear memory retrieval appeared to be intact. Limitations In future studies, additional phenotypes might be identified and a detailed characterization of direct reciprocal social interaction behavior might help to reveal effects of Myt1l haploinsufficiency on social behavior in juvenile and adult mice. Conclusions Behavioral alterations in Myt1l haploinsufficient mice recapitulate several clinical phenotypes observed in humans carrying heterozygous MYT1L mutations and thus serve as an informative model of the human MYT1L syndrome.
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allfields	10.1186/s13229-022-00497-3 doi (DE-627)SPR050699652 (SPR)s13229-022-00497-3-e DE-627 ger DE-627 rakwb eng Wöhr, Markus verfasserin (orcid)0000-0001-6986-5684 aut Myt1l haploinsufficiency leads to obesity and multifaceted behavioral alterations in mice 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2022 Background The zinc finger domain containing transcription factor Myt1l is tightly associated with neuronal identity and is the only transcription factor known that is both neuron-specific and expressed in all neuronal subtypes. We identified Myt1l as a powerful reprogramming factor that, in combination with the proneural bHLH factor Ascl1, could induce neuronal fate in fibroblasts. Molecularly, we found it to repress many non-neuronal gene programs, explaining its supportive role to induce and safeguard neuronal identity in combination with proneural bHLH transcriptional activators. Moreover, human genetics studies found MYT1L mutations to cause intellectual disability and autism spectrum disorder often coupled with obesity. Methods Here, we generated and characterized Myt1l-deficient mice. A comprehensive, longitudinal behavioral phenotyping approach was applied. Results Myt1l was necessary for survival beyond 24 h but not for overall histological brain organization. Myt1l heterozygous mice became increasingly overweight and exhibited multifaceted behavioral alterations. In mouse pups, Myt1l haploinsufficiency caused mild alterations in early socio-affective communication through ultrasonic vocalizations. In adulthood, Myt1l heterozygous mice displayed hyperactivity due to impaired habituation learning. Motor performance was reduced in Myt1l heterozygous mice despite intact motor learning, possibly due to muscular hypotonia. While anxiety-related behavior was reduced, acoustic startle reactivity was enhanced, in line with higher sensitivity to loud sound. Finally, Myt1l haploinsufficiency had a negative impact on contextual fear memory retrieval, while cued fear memory retrieval appeared to be intact. Limitations In future studies, additional phenotypes might be identified and a detailed characterization of direct reciprocal social interaction behavior might help to reveal effects of Myt1l haploinsufficiency on social behavior in juvenile and adult mice. Conclusions Behavioral alterations in Myt1l haploinsufficient mice recapitulate several clinical phenotypes observed in humans carrying heterozygous MYT1L mutations and thus serve as an informative model of the human MYT1L syndrome. Transcription factor (dpeaa)DE-He213 Autism (dpeaa)DE-He213 Obesity (dpeaa)DE-He213 Social behavior (dpeaa)DE-He213 Ultrasonic vocalization (dpeaa)DE-He213 Fong, Wendy M. (orcid)0000-0001-5732-7344 aut Janas, Justyna A. (orcid)0000-0001-9840-9928 aut Mall, Moritz (orcid)0000-0002-1278-2594 aut Thome, Christian (orcid)0000-0002-3344-8683 aut Vangipuram, Madhuri (orcid)0000-0001-7271-2689 aut Meng, Lingjun (orcid)0000-0003-2359-1555 aut Südhof, Thomas C. (orcid)0000-0003-3361-9275 aut Wernig, Marius (orcid)0000-0002-5309-515X aut Enthalten in Molecular autism London : BioMed Central, 2010 13(2022), 1 vom: 10. Mai (DE-627)620141522 (DE-600)2540930-X 2040-2392 nnns volume:13 year:2022 number:1 day:10 month:05 https://dx.doi.org/10.1186/s13229-022-00497-3 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 13 2022 1 10 05
spelling	10.1186/s13229-022-00497-3 doi (DE-627)SPR050699652 (SPR)s13229-022-00497-3-e DE-627 ger DE-627 rakwb eng Wöhr, Markus verfasserin (orcid)0000-0001-6986-5684 aut Myt1l haploinsufficiency leads to obesity and multifaceted behavioral alterations in mice 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2022 Background The zinc finger domain containing transcription factor Myt1l is tightly associated with neuronal identity and is the only transcription factor known that is both neuron-specific and expressed in all neuronal subtypes. We identified Myt1l as a powerful reprogramming factor that, in combination with the proneural bHLH factor Ascl1, could induce neuronal fate in fibroblasts. Molecularly, we found it to repress many non-neuronal gene programs, explaining its supportive role to induce and safeguard neuronal identity in combination with proneural bHLH transcriptional activators. Moreover, human genetics studies found MYT1L mutations to cause intellectual disability and autism spectrum disorder often coupled with obesity. Methods Here, we generated and characterized Myt1l-deficient mice. A comprehensive, longitudinal behavioral phenotyping approach was applied. Results Myt1l was necessary for survival beyond 24 h but not for overall histological brain organization. Myt1l heterozygous mice became increasingly overweight and exhibited multifaceted behavioral alterations. In mouse pups, Myt1l haploinsufficiency caused mild alterations in early socio-affective communication through ultrasonic vocalizations. In adulthood, Myt1l heterozygous mice displayed hyperactivity due to impaired habituation learning. Motor performance was reduced in Myt1l heterozygous mice despite intact motor learning, possibly due to muscular hypotonia. While anxiety-related behavior was reduced, acoustic startle reactivity was enhanced, in line with higher sensitivity to loud sound. Finally, Myt1l haploinsufficiency had a negative impact on contextual fear memory retrieval, while cued fear memory retrieval appeared to be intact. Limitations In future studies, additional phenotypes might be identified and a detailed characterization of direct reciprocal social interaction behavior might help to reveal effects of Myt1l haploinsufficiency on social behavior in juvenile and adult mice. Conclusions Behavioral alterations in Myt1l haploinsufficient mice recapitulate several clinical phenotypes observed in humans carrying heterozygous MYT1L mutations and thus serve as an informative model of the human MYT1L syndrome. Transcription factor (dpeaa)DE-He213 Autism (dpeaa)DE-He213 Obesity (dpeaa)DE-He213 Social behavior (dpeaa)DE-He213 Ultrasonic vocalization (dpeaa)DE-He213 Fong, Wendy M. (orcid)0000-0001-5732-7344 aut Janas, Justyna A. (orcid)0000-0001-9840-9928 aut Mall, Moritz (orcid)0000-0002-1278-2594 aut Thome, Christian (orcid)0000-0002-3344-8683 aut Vangipuram, Madhuri (orcid)0000-0001-7271-2689 aut Meng, Lingjun (orcid)0000-0003-2359-1555 aut Südhof, Thomas C. (orcid)0000-0003-3361-9275 aut Wernig, Marius (orcid)0000-0002-5309-515X aut Enthalten in Molecular autism London : BioMed Central, 2010 13(2022), 1 vom: 10. Mai (DE-627)620141522 (DE-600)2540930-X 2040-2392 nnns volume:13 year:2022 number:1 day:10 month:05 https://dx.doi.org/10.1186/s13229-022-00497-3 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 13 2022 1 10 05
allfields_unstemmed	10.1186/s13229-022-00497-3 doi (DE-627)SPR050699652 (SPR)s13229-022-00497-3-e DE-627 ger DE-627 rakwb eng Wöhr, Markus verfasserin (orcid)0000-0001-6986-5684 aut Myt1l haploinsufficiency leads to obesity and multifaceted behavioral alterations in mice 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2022 Background The zinc finger domain containing transcription factor Myt1l is tightly associated with neuronal identity and is the only transcription factor known that is both neuron-specific and expressed in all neuronal subtypes. We identified Myt1l as a powerful reprogramming factor that, in combination with the proneural bHLH factor Ascl1, could induce neuronal fate in fibroblasts. Molecularly, we found it to repress many non-neuronal gene programs, explaining its supportive role to induce and safeguard neuronal identity in combination with proneural bHLH transcriptional activators. Moreover, human genetics studies found MYT1L mutations to cause intellectual disability and autism spectrum disorder often coupled with obesity. Methods Here, we generated and characterized Myt1l-deficient mice. A comprehensive, longitudinal behavioral phenotyping approach was applied. Results Myt1l was necessary for survival beyond 24 h but not for overall histological brain organization. Myt1l heterozygous mice became increasingly overweight and exhibited multifaceted behavioral alterations. In mouse pups, Myt1l haploinsufficiency caused mild alterations in early socio-affective communication through ultrasonic vocalizations. In adulthood, Myt1l heterozygous mice displayed hyperactivity due to impaired habituation learning. Motor performance was reduced in Myt1l heterozygous mice despite intact motor learning, possibly due to muscular hypotonia. While anxiety-related behavior was reduced, acoustic startle reactivity was enhanced, in line with higher sensitivity to loud sound. Finally, Myt1l haploinsufficiency had a negative impact on contextual fear memory retrieval, while cued fear memory retrieval appeared to be intact. Limitations In future studies, additional phenotypes might be identified and a detailed characterization of direct reciprocal social interaction behavior might help to reveal effects of Myt1l haploinsufficiency on social behavior in juvenile and adult mice. Conclusions Behavioral alterations in Myt1l haploinsufficient mice recapitulate several clinical phenotypes observed in humans carrying heterozygous MYT1L mutations and thus serve as an informative model of the human MYT1L syndrome. Transcription factor (dpeaa)DE-He213 Autism (dpeaa)DE-He213 Obesity (dpeaa)DE-He213 Social behavior (dpeaa)DE-He213 Ultrasonic vocalization (dpeaa)DE-He213 Fong, Wendy M. (orcid)0000-0001-5732-7344 aut Janas, Justyna A. (orcid)0000-0001-9840-9928 aut Mall, Moritz (orcid)0000-0002-1278-2594 aut Thome, Christian (orcid)0000-0002-3344-8683 aut Vangipuram, Madhuri (orcid)0000-0001-7271-2689 aut Meng, Lingjun (orcid)0000-0003-2359-1555 aut Südhof, Thomas C. (orcid)0000-0003-3361-9275 aut Wernig, Marius (orcid)0000-0002-5309-515X aut Enthalten in Molecular autism London : BioMed Central, 2010 13(2022), 1 vom: 10. Mai (DE-627)620141522 (DE-600)2540930-X 2040-2392 nnns volume:13 year:2022 number:1 day:10 month:05 https://dx.doi.org/10.1186/s13229-022-00497-3 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 13 2022 1 10 05
allfieldsGer	10.1186/s13229-022-00497-3 doi (DE-627)SPR050699652 (SPR)s13229-022-00497-3-e DE-627 ger DE-627 rakwb eng Wöhr, Markus verfasserin (orcid)0000-0001-6986-5684 aut Myt1l haploinsufficiency leads to obesity and multifaceted behavioral alterations in mice 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2022 Background The zinc finger domain containing transcription factor Myt1l is tightly associated with neuronal identity and is the only transcription factor known that is both neuron-specific and expressed in all neuronal subtypes. We identified Myt1l as a powerful reprogramming factor that, in combination with the proneural bHLH factor Ascl1, could induce neuronal fate in fibroblasts. Molecularly, we found it to repress many non-neuronal gene programs, explaining its supportive role to induce and safeguard neuronal identity in combination with proneural bHLH transcriptional activators. Moreover, human genetics studies found MYT1L mutations to cause intellectual disability and autism spectrum disorder often coupled with obesity. Methods Here, we generated and characterized Myt1l-deficient mice. A comprehensive, longitudinal behavioral phenotyping approach was applied. Results Myt1l was necessary for survival beyond 24 h but not for overall histological brain organization. Myt1l heterozygous mice became increasingly overweight and exhibited multifaceted behavioral alterations. In mouse pups, Myt1l haploinsufficiency caused mild alterations in early socio-affective communication through ultrasonic vocalizations. In adulthood, Myt1l heterozygous mice displayed hyperactivity due to impaired habituation learning. Motor performance was reduced in Myt1l heterozygous mice despite intact motor learning, possibly due to muscular hypotonia. While anxiety-related behavior was reduced, acoustic startle reactivity was enhanced, in line with higher sensitivity to loud sound. Finally, Myt1l haploinsufficiency had a negative impact on contextual fear memory retrieval, while cued fear memory retrieval appeared to be intact. Limitations In future studies, additional phenotypes might be identified and a detailed characterization of direct reciprocal social interaction behavior might help to reveal effects of Myt1l haploinsufficiency on social behavior in juvenile and adult mice. Conclusions Behavioral alterations in Myt1l haploinsufficient mice recapitulate several clinical phenotypes observed in humans carrying heterozygous MYT1L mutations and thus serve as an informative model of the human MYT1L syndrome. Transcription factor (dpeaa)DE-He213 Autism (dpeaa)DE-He213 Obesity (dpeaa)DE-He213 Social behavior (dpeaa)DE-He213 Ultrasonic vocalization (dpeaa)DE-He213 Fong, Wendy M. (orcid)0000-0001-5732-7344 aut Janas, Justyna A. (orcid)0000-0001-9840-9928 aut Mall, Moritz (orcid)0000-0002-1278-2594 aut Thome, Christian (orcid)0000-0002-3344-8683 aut Vangipuram, Madhuri (orcid)0000-0001-7271-2689 aut Meng, Lingjun (orcid)0000-0003-2359-1555 aut Südhof, Thomas C. (orcid)0000-0003-3361-9275 aut Wernig, Marius (orcid)0000-0002-5309-515X aut Enthalten in Molecular autism London : BioMed Central, 2010 13(2022), 1 vom: 10. Mai (DE-627)620141522 (DE-600)2540930-X 2040-2392 nnns volume:13 year:2022 number:1 day:10 month:05 https://dx.doi.org/10.1186/s13229-022-00497-3 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 13 2022 1 10 05
allfieldsSound	10.1186/s13229-022-00497-3 doi (DE-627)SPR050699652 (SPR)s13229-022-00497-3-e DE-627 ger DE-627 rakwb eng Wöhr, Markus verfasserin (orcid)0000-0001-6986-5684 aut Myt1l haploinsufficiency leads to obesity and multifaceted behavioral alterations in mice 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2022 Background The zinc finger domain containing transcription factor Myt1l is tightly associated with neuronal identity and is the only transcription factor known that is both neuron-specific and expressed in all neuronal subtypes. We identified Myt1l as a powerful reprogramming factor that, in combination with the proneural bHLH factor Ascl1, could induce neuronal fate in fibroblasts. Molecularly, we found it to repress many non-neuronal gene programs, explaining its supportive role to induce and safeguard neuronal identity in combination with proneural bHLH transcriptional activators. Moreover, human genetics studies found MYT1L mutations to cause intellectual disability and autism spectrum disorder often coupled with obesity. Methods Here, we generated and characterized Myt1l-deficient mice. A comprehensive, longitudinal behavioral phenotyping approach was applied. Results Myt1l was necessary for survival beyond 24 h but not for overall histological brain organization. Myt1l heterozygous mice became increasingly overweight and exhibited multifaceted behavioral alterations. In mouse pups, Myt1l haploinsufficiency caused mild alterations in early socio-affective communication through ultrasonic vocalizations. In adulthood, Myt1l heterozygous mice displayed hyperactivity due to impaired habituation learning. Motor performance was reduced in Myt1l heterozygous mice despite intact motor learning, possibly due to muscular hypotonia. While anxiety-related behavior was reduced, acoustic startle reactivity was enhanced, in line with higher sensitivity to loud sound. Finally, Myt1l haploinsufficiency had a negative impact on contextual fear memory retrieval, while cued fear memory retrieval appeared to be intact. Limitations In future studies, additional phenotypes might be identified and a detailed characterization of direct reciprocal social interaction behavior might help to reveal effects of Myt1l haploinsufficiency on social behavior in juvenile and adult mice. Conclusions Behavioral alterations in Myt1l haploinsufficient mice recapitulate several clinical phenotypes observed in humans carrying heterozygous MYT1L mutations and thus serve as an informative model of the human MYT1L syndrome. Transcription factor (dpeaa)DE-He213 Autism (dpeaa)DE-He213 Obesity (dpeaa)DE-He213 Social behavior (dpeaa)DE-He213 Ultrasonic vocalization (dpeaa)DE-He213 Fong, Wendy M. (orcid)0000-0001-5732-7344 aut Janas, Justyna A. (orcid)0000-0001-9840-9928 aut Mall, Moritz (orcid)0000-0002-1278-2594 aut Thome, Christian (orcid)0000-0002-3344-8683 aut Vangipuram, Madhuri (orcid)0000-0001-7271-2689 aut Meng, Lingjun (orcid)0000-0003-2359-1555 aut Südhof, Thomas C. (orcid)0000-0003-3361-9275 aut Wernig, Marius (orcid)0000-0002-5309-515X aut Enthalten in Molecular autism London : BioMed Central, 2010 13(2022), 1 vom: 10. Mai (DE-627)620141522 (DE-600)2540930-X 2040-2392 nnns volume:13 year:2022 number:1 day:10 month:05 https://dx.doi.org/10.1186/s13229-022-00497-3 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 13 2022 1 10 05
language	English
source	Enthalten in Molecular autism 13(2022), 1 vom: 10. Mai volume:13 year:2022 number:1 day:10 month:05
sourceStr	Enthalten in Molecular autism 13(2022), 1 vom: 10. Mai volume:13 year:2022 number:1 day:10 month:05
format_phy_str_mv	Article
institution	findex.gbv.de
topic_facet	Transcription factor Autism Obesity Social behavior Ultrasonic vocalization
isfreeaccess_bool	true
container_title	Molecular autism
authorswithroles_txt_mv	Wöhr, Markus @@aut@@ Fong, Wendy M. @@aut@@ Janas, Justyna A. @@aut@@ Mall, Moritz @@aut@@ Thome, Christian @@aut@@ Vangipuram, Madhuri @@aut@@ Meng, Lingjun @@aut@@ Südhof, Thomas C. @@aut@@ Wernig, Marius @@aut@@
publishDateDaySort_date	2022-05-10T00:00:00Z
hierarchy_top_id	620141522
id	SPR050699652
language_de	englisch
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We identified Myt1l as a powerful reprogramming factor that, in combination with the proneural bHLH factor Ascl1, could induce neuronal fate in fibroblasts. Molecularly, we found it to repress many non-neuronal gene programs, explaining its supportive role to induce and safeguard neuronal identity in combination with proneural bHLH transcriptional activators. Moreover, human genetics studies found MYT1L mutations to cause intellectual disability and autism spectrum disorder often coupled with obesity. Methods Here, we generated and characterized Myt1l-deficient mice. A comprehensive, longitudinal behavioral phenotyping approach was applied. Results Myt1l was necessary for survival beyond 24 h but not for overall histological brain organization. Myt1l heterozygous mice became increasingly overweight and exhibited multifaceted behavioral alterations. In mouse pups, Myt1l haploinsufficiency caused mild alterations in early socio-affective communication through ultrasonic vocalizations. In adulthood, Myt1l heterozygous mice displayed hyperactivity due to impaired habituation learning. Motor performance was reduced in Myt1l heterozygous mice despite intact motor learning, possibly due to muscular hypotonia. While anxiety-related behavior was reduced, acoustic startle reactivity was enhanced, in line with higher sensitivity to loud sound. Finally, Myt1l haploinsufficiency had a negative impact on contextual fear memory retrieval, while cued fear memory retrieval appeared to be intact. Limitations In future studies, additional phenotypes might be identified and a detailed characterization of direct reciprocal social interaction behavior might help to reveal effects of Myt1l haploinsufficiency on social behavior in juvenile and adult mice. Conclusions Behavioral alterations in Myt1l haploinsufficient mice recapitulate several clinical phenotypes observed in humans carrying heterozygous MYT1L mutations and thus serve as an informative model of the human MYT1L syndrome.</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Transcription factor</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Autism</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Obesity</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Social behavior</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Ultrasonic vocalization</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Fong, Wendy M.</subfield><subfield code="0">(orcid)0000-0001-5732-7344</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Janas, Justyna A.</subfield><subfield code="0">(orcid)0000-0001-9840-9928</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Mall, Moritz</subfield><subfield code="0">(orcid)0000-0002-1278-2594</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Thome, Christian</subfield><subfield code="0">(orcid)0000-0002-3344-8683</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Vangipuram, Madhuri</subfield><subfield code="0">(orcid)0000-0001-7271-2689</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Meng, Lingjun</subfield><subfield code="0">(orcid)0000-0003-2359-1555</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Südhof, Thomas C.</subfield><subfield code="0">(orcid)0000-0003-3361-9275</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Wernig, Marius</subfield><subfield code="0">(orcid)0000-0002-5309-515X</subfield><subfield code="4">aut</subfield></datafield><datafield tag="773" ind1="0" ind2="8"><subfield code="i">Enthalten in</subfield><subfield code="t">Molecular autism</subfield><subfield code="d">London : BioMed Central, 2010</subfield><subfield code="g">13(2022), 1 vom: 10. 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author	Wöhr, Markus
spellingShingle	Wöhr, Markus misc Transcription factor misc Autism misc Obesity misc Social behavior misc Ultrasonic vocalization Myt1l haploinsufficiency leads to obesity and multifaceted behavioral alterations in mice
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topic_title	Myt1l haploinsufficiency leads to obesity and multifaceted behavioral alterations in mice Transcription factor (dpeaa)DE-He213 Autism (dpeaa)DE-He213 Obesity (dpeaa)DE-He213 Social behavior (dpeaa)DE-He213 Ultrasonic vocalization (dpeaa)DE-He213
topic	misc Transcription factor misc Autism misc Obesity misc Social behavior misc Ultrasonic vocalization
topic_unstemmed	misc Transcription factor misc Autism misc Obesity misc Social behavior misc Ultrasonic vocalization
topic_browse	misc Transcription factor misc Autism misc Obesity misc Social behavior misc Ultrasonic vocalization
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title	Myt1l haploinsufficiency leads to obesity and multifaceted behavioral alterations in mice
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title_full	Myt1l haploinsufficiency leads to obesity and multifaceted behavioral alterations in mice
author_sort	Wöhr, Markus
journal	Molecular autism
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author_browse	Wöhr, Markus Fong, Wendy M. Janas, Justyna A. Mall, Moritz Thome, Christian Vangipuram, Madhuri Meng, Lingjun Südhof, Thomas C. Wernig, Marius
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title_sort	myt1l haploinsufficiency leads to obesity and multifaceted behavioral alterations in mice
title_auth	Myt1l haploinsufficiency leads to obesity and multifaceted behavioral alterations in mice
abstract	Background The zinc finger domain containing transcription factor Myt1l is tightly associated with neuronal identity and is the only transcription factor known that is both neuron-specific and expressed in all neuronal subtypes. We identified Myt1l as a powerful reprogramming factor that, in combination with the proneural bHLH factor Ascl1, could induce neuronal fate in fibroblasts. Molecularly, we found it to repress many non-neuronal gene programs, explaining its supportive role to induce and safeguard neuronal identity in combination with proneural bHLH transcriptional activators. Moreover, human genetics studies found MYT1L mutations to cause intellectual disability and autism spectrum disorder often coupled with obesity. Methods Here, we generated and characterized Myt1l-deficient mice. A comprehensive, longitudinal behavioral phenotyping approach was applied. Results Myt1l was necessary for survival beyond 24 h but not for overall histological brain organization. Myt1l heterozygous mice became increasingly overweight and exhibited multifaceted behavioral alterations. In mouse pups, Myt1l haploinsufficiency caused mild alterations in early socio-affective communication through ultrasonic vocalizations. In adulthood, Myt1l heterozygous mice displayed hyperactivity due to impaired habituation learning. Motor performance was reduced in Myt1l heterozygous mice despite intact motor learning, possibly due to muscular hypotonia. While anxiety-related behavior was reduced, acoustic startle reactivity was enhanced, in line with higher sensitivity to loud sound. Finally, Myt1l haploinsufficiency had a negative impact on contextual fear memory retrieval, while cued fear memory retrieval appeared to be intact. Limitations In future studies, additional phenotypes might be identified and a detailed characterization of direct reciprocal social interaction behavior might help to reveal effects of Myt1l haploinsufficiency on social behavior in juvenile and adult mice. Conclusions Behavioral alterations in Myt1l haploinsufficient mice recapitulate several clinical phenotypes observed in humans carrying heterozygous MYT1L mutations and thus serve as an informative model of the human MYT1L syndrome. © The Author(s) 2022
abstractGer	Background The zinc finger domain containing transcription factor Myt1l is tightly associated with neuronal identity and is the only transcription factor known that is both neuron-specific and expressed in all neuronal subtypes. We identified Myt1l as a powerful reprogramming factor that, in combination with the proneural bHLH factor Ascl1, could induce neuronal fate in fibroblasts. Molecularly, we found it to repress many non-neuronal gene programs, explaining its supportive role to induce and safeguard neuronal identity in combination with proneural bHLH transcriptional activators. Moreover, human genetics studies found MYT1L mutations to cause intellectual disability and autism spectrum disorder often coupled with obesity. Methods Here, we generated and characterized Myt1l-deficient mice. A comprehensive, longitudinal behavioral phenotyping approach was applied. Results Myt1l was necessary for survival beyond 24 h but not for overall histological brain organization. Myt1l heterozygous mice became increasingly overweight and exhibited multifaceted behavioral alterations. In mouse pups, Myt1l haploinsufficiency caused mild alterations in early socio-affective communication through ultrasonic vocalizations. In adulthood, Myt1l heterozygous mice displayed hyperactivity due to impaired habituation learning. Motor performance was reduced in Myt1l heterozygous mice despite intact motor learning, possibly due to muscular hypotonia. While anxiety-related behavior was reduced, acoustic startle reactivity was enhanced, in line with higher sensitivity to loud sound. Finally, Myt1l haploinsufficiency had a negative impact on contextual fear memory retrieval, while cued fear memory retrieval appeared to be intact. Limitations In future studies, additional phenotypes might be identified and a detailed characterization of direct reciprocal social interaction behavior might help to reveal effects of Myt1l haploinsufficiency on social behavior in juvenile and adult mice. Conclusions Behavioral alterations in Myt1l haploinsufficient mice recapitulate several clinical phenotypes observed in humans carrying heterozygous MYT1L mutations and thus serve as an informative model of the human MYT1L syndrome. © The Author(s) 2022
abstract_unstemmed	Background The zinc finger domain containing transcription factor Myt1l is tightly associated with neuronal identity and is the only transcription factor known that is both neuron-specific and expressed in all neuronal subtypes. We identified Myt1l as a powerful reprogramming factor that, in combination with the proneural bHLH factor Ascl1, could induce neuronal fate in fibroblasts. Molecularly, we found it to repress many non-neuronal gene programs, explaining its supportive role to induce and safeguard neuronal identity in combination with proneural bHLH transcriptional activators. Moreover, human genetics studies found MYT1L mutations to cause intellectual disability and autism spectrum disorder often coupled with obesity. Methods Here, we generated and characterized Myt1l-deficient mice. A comprehensive, longitudinal behavioral phenotyping approach was applied. Results Myt1l was necessary for survival beyond 24 h but not for overall histological brain organization. Myt1l heterozygous mice became increasingly overweight and exhibited multifaceted behavioral alterations. In mouse pups, Myt1l haploinsufficiency caused mild alterations in early socio-affective communication through ultrasonic vocalizations. In adulthood, Myt1l heterozygous mice displayed hyperactivity due to impaired habituation learning. Motor performance was reduced in Myt1l heterozygous mice despite intact motor learning, possibly due to muscular hypotonia. While anxiety-related behavior was reduced, acoustic startle reactivity was enhanced, in line with higher sensitivity to loud sound. Finally, Myt1l haploinsufficiency had a negative impact on contextual fear memory retrieval, while cued fear memory retrieval appeared to be intact. Limitations In future studies, additional phenotypes might be identified and a detailed characterization of direct reciprocal social interaction behavior might help to reveal effects of Myt1l haploinsufficiency on social behavior in juvenile and adult mice. Conclusions Behavioral alterations in Myt1l haploinsufficient mice recapitulate several clinical phenotypes observed in humans carrying heterozygous MYT1L mutations and thus serve as an informative model of the human MYT1L syndrome. © The Author(s) 2022
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container_issue	1
title_short	Myt1l haploinsufficiency leads to obesity and multifaceted behavioral alterations in mice
url	https://dx.doi.org/10.1186/s13229-022-00497-3
remote_bool	true
author2	Fong, Wendy M. Janas, Justyna A. Mall, Moritz Thome, Christian Vangipuram, Madhuri Meng, Lingjun Südhof, Thomas C. Wernig, Marius
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Myt1l haploinsufficiency leads to obesity and multifaceted behavioral alterations in mice

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