Regulation of GABAergic neuron identity and diversity in the developing midbrain

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http://urn.fi/URN:ISBN:978-952-92-7548-9
Title: Regulation of GABAergic neuron identity and diversity in the developing midbrain
Author: Achim, Kaia
Contributor: University of Helsinki, Faculty of Biological and Environmental Sciences, Department of Biosciences
Institute of biotechnology
Thesis level: Doctoral dissertation (article-based)
Abstract: Gamma-aminobutyric acid (GABA) is the most abundant inhibitory neurotransmitter in the vertebrate brain. In the midbrain, GABAergic neurons contribute to the regulation of locomotion, nociception, defensive behaviours, fear and anxiety, as well as sensing reward and addiction. Despite the clinical relevance of this group of neurons, the mechanisms regulating their development are largely unknown. In addition, their migration and connectivity patterns are poorly characterized. This study focuses on the molecular mechanisms specifying the GABAergic fate, and the developmental origins of midbrain GABAergic neurons. First, we have characterized the function of a zink-finger transcription factor Gata2. Using a tissue-specific mutagenesis in mouse midbrain and anteror hindbrain, we showed that Gata2 is a crucial determinant of the GABAergic fate in midbrain. In the absence of Gata2, no GABAergic neurons are produced from the otherwise competent midbrain neuroepithelium. Instead, the Gata2-mutant cells acquire a glutamatergic neuron phenotype. Ectopic expression of Gata2 was also sufficient to induce GABAergic in chicken midbrain. Second, we have analyzed the midbrain phenotype of mice mutant for a proneural gene Ascl1, and described the variable and region-dependent requirements for Ascl1 in the midbrain GABAergic neurogenesis. These studies also have implications on the origin of distinct anatomical and functional GABAergic subpopulations in midbrain. Third, we have identified unique developmental properties of GABAergic neurons that are associated with the midbrain dopaminergic nuclei, the substantia nigra pars reticulata (SNpr) and ventral tegmental area (VTA). Namely, the genetic regulation of GABAergic fate in these cells is distinct from the rest of midbrain. In accordance to this phenomenon, our detailed fate-mapping analyses indicated that the SNpr-VTA GABAergic neurons are generated outside midbrain, in the neuroepithelium of anterior hindbrain.Keskiaivojen GABAergiset hermosolut ovat keskeisiä mm. mielialan ja motivaation säätelyssä. Ne ovat myös osallisina psyykkisissä sairauksissa kuten ahdistuksessa ja masennuksessa sekä erilaisten riippuvaisuuksien synnyssä. Lääketieteellisestä merkityksestään huolimatta keskiaivojen GABAergiset hermosolut tunnetaan huonosti molekulaariselta koostumukseltaan ja yksilönkehityksen aikaisilta säätelymekanismeiltaan. Tässä tutkimuksessa olemme kartoittaneet keskiaivojen alueet, jotka tuottavat GABAergisiä hermosoluja. Hiiren ja kanan alkioita tutkimusmalleina käyttäen olemme osoittaneet miten tietyt transkriptiotekijät ohjaavat GABAergisen soluidentiteetin syntyä. Lisäksi olemme karakterisoineet eri GABAergisten hermosolujen osapopulaatioiden ominaisuuksia, keskittyen muista keskiaivon GABAergisista soluista poikkeavien ventraalisten GABAergisten hermosolujen syntyhistoriaan. Tutkimus lisää ymmärrystämme keskiaivojen GABAergisten hermosolujen kehityksestä ja monimutkaisuudesta.
URI: URN:ISBN:978-952-92-7548-9
http://hdl.handle.net/10138/22413
Date: 2010-09-03
Subject: fysiologia ja neurotiede
Rights: This publication is copyrighted. You may download, display and print it for Your own personal use. Commercial use is prohibited.


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