Neurodevelopmental approach in the study of the function of Wfs1 and Lsamp, potential targets in the regulation of emotional behaviour
Date
2018-06-14
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Abstract
Psühhiaatriliste häirete kujunemises mängib olulist rolli aju areng. Geenid, mis osalevad emotsioonidega seotud ajupiirkondade arengus ja funktsioneerimises, on olulised psühhiaatriliste häirete seisukohalt. Wfs1 ja Lsamp geenid osalevad hirmu- ja ärevuskäitumise regulatsioonis. Wfs1 (Wolframi sündroom 1), nagu nimigi ütleb, on seotud samanimelise haruldase sündroomiga, mille sümptomid on diabetes insipidus, diabetes mellitus, nägemisnärvi kärbumine ja sensorineuraalne kurtus, sageli kaasnevad ka psühhiaatrilised häired. Wfs1 valk mängib olulist rolli insuliini sekretsioonis ja pankrease β-rakkude ellujäämise tagamises, selle funktsioonist ajus on vähem teada. Lsamp (limbilise süsteemiga seotud membraanivalk) osaleb neuriitide väljakasvu, aksonite sihtmärgini jõudmise ja sünaptogeneesi reguleerimises. Lsamp geenil on kaks evolutsiooniliselt konserveerunud alternatiivset esimest eksonit koos eraldi promootoritega, sellise struktuuri funktsionaalne tähtsus on teadmata. Nii Wfs1 kui Lsamp geeni puhul on näidatud kindlate alleelide seotust meeleolu- ja ärevushäirete, skisofreenia ja suitsidaalsusega. Enda doktoritöös uurisin Wfs1 ja Lsamp`i funktsiooni arengulisest vaatevinklist. Selgus, et Wfs1 ekspressioon on evolutsiooniliselt konserveerunud dopamiinergilist sisendit saavates ajupiirkondades, ning et Wfs1 suhtes puudulike hiirte hipokampuses on D1-tüüpi dopamiini retseptorite hulk suurenenud. Arengu käigus ekspresseerus Wfs1 ajutiselt paljudes ajupiirkondades; see laialdane ekspressioon polnud seotud arengulise endoplasmaatilise retiikulumi stressi vastuse regulatsiooniga, mis on üks Wfs1 põhilisi funktsioone täiskasvanud organismis. Lsamp`i puhul näitasime, et selle alternatiivsed promootorid on aktiivsed erinevate funktsioonidega ajupiirkondades: 1a-promootor on põhiline limbilises süsteemis, samas kui 1b-promootori aktiivsus piiritleb sensoorseid juhteteid. Lsamp`i promootorite aktiivsus hiirte hipokampuses, ventraalses striatumis ja temporaalsagaras korreleerus sotsiaalse- ja ärevusega seotud käitumise näitajatega. Saadud tulemused aitavad paremini mõista Wfs1 ja Lsamp`i rolli psühhiaatriliste häirete väljakujunemises ning näitavad suunda edasisteks uuringuteks.
Genes that are involved in the development and functioning of the emotional circuits of the brain are highly susceptible targets in psychiatric diseases. Wfs1 and Lsamp, two genes studied in the present thesis, are both involved in the regulation of anxiety- and fear-related behaviour in the adult brain. Wfs1 (Wolfram syndrome 1) is a causative gene for Wolfram syndrome, a rare genetic disorder characterized by diabetes insipidus, diabetes mellitus, optic atrophy and sensorineural deafness. Often, the core symptoms are accompanied by psychiatric manifestations. Wfs1 is important for the survival and functioning of pancreatic β-cells, its roles in the nervous system are not well understood. Lsamp (Limbic system associated membrane protein) is involved in regulating neurite outgrowth, axon targeting and synaptogenesis in the limbic system. Lsamp has two alternative first exons with separate promoters, the role of this conserved gene structure is unknown. Allelic variants of both, Wfs1 and Lsamp, are associated with depression, anxiety disorders, bipolar disorder, schizophrenia and suicidality. We took advantage of the neurodevelopmental approach to study the functions of Wfs1 and Lsamp in the brain. Wfs1 showed evolutionarily conserved expression in the dopaminoceptive brain regions. Relating to this, Wfs1-deficient mice had increased number of D1-type dopamine receptor ligand binding sites in the hippocampi compared to wild-type mice. During the development, Wfs1 was transiently expressed in many brain regions. The widespread expression of Wfs1 in early postnatal mouse brain was not involved in the regulation of developmental endoplasmic reticulum stress, which has previously been shown to be one of the main functions of Wfs1 in the adult organism. The activity pattern of the two alternative promoters of Lsamp was complementary in the mouse brain: 1a promoter was prevailing in the limbic-related structures, while the activity of 1b promoter mainly delineated sensory pathways. The activity of Lsamp promoters in the hippocampus, ventral striatum and temporal lobe correlated with measures of anxiety and social behaviour of mice. The present results help to understand the role of Wfs1 and Lsamp in the context of psychiatric diseases and point direction for further research.
Genes that are involved in the development and functioning of the emotional circuits of the brain are highly susceptible targets in psychiatric diseases. Wfs1 and Lsamp, two genes studied in the present thesis, are both involved in the regulation of anxiety- and fear-related behaviour in the adult brain. Wfs1 (Wolfram syndrome 1) is a causative gene for Wolfram syndrome, a rare genetic disorder characterized by diabetes insipidus, diabetes mellitus, optic atrophy and sensorineural deafness. Often, the core symptoms are accompanied by psychiatric manifestations. Wfs1 is important for the survival and functioning of pancreatic β-cells, its roles in the nervous system are not well understood. Lsamp (Limbic system associated membrane protein) is involved in regulating neurite outgrowth, axon targeting and synaptogenesis in the limbic system. Lsamp has two alternative first exons with separate promoters, the role of this conserved gene structure is unknown. Allelic variants of both, Wfs1 and Lsamp, are associated with depression, anxiety disorders, bipolar disorder, schizophrenia and suicidality. We took advantage of the neurodevelopmental approach to study the functions of Wfs1 and Lsamp in the brain. Wfs1 showed evolutionarily conserved expression in the dopaminoceptive brain regions. Relating to this, Wfs1-deficient mice had increased number of D1-type dopamine receptor ligand binding sites in the hippocampi compared to wild-type mice. During the development, Wfs1 was transiently expressed in many brain regions. The widespread expression of Wfs1 in early postnatal mouse brain was not involved in the regulation of developmental endoplasmic reticulum stress, which has previously been shown to be one of the main functions of Wfs1 in the adult organism. The activity pattern of the two alternative promoters of Lsamp was complementary in the mouse brain: 1a promoter was prevailing in the limbic-related structures, while the activity of 1b promoter mainly delineated sensory pathways. The activity of Lsamp promoters in the hippocampus, ventral striatum and temporal lobe correlated with measures of anxiety and social behaviour of mice. The present results help to understand the role of Wfs1 and Lsamp in the context of psychiatric diseases and point direction for further research.
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Keywords
gene expression, genes, amygdaloid body, neurogenesis, development of nervous system, social behavior, behavioral and emotional disorders