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A structurally plastic extension of the homeodomain recognition helix orchestrates central Hox protein activity
Institut de Biologie du Développement de Marseille Luminy, IBDML, CNRS, Université de la Méditerranée, Parc Scientifique de Luminy, Case 907 13288 Marseille Cedex 09, France.
Institut de Biologie du Développement de Marseille Luminy, IBDML, CNRS, Université de la Méditerranée, Parc Scientifique de Luminy, Case 907 13288 Marseille Cedex 09, France.
AFMB, Université de la Méditerranée, Parc Scientifique de LuminyMarseille Cedex 09, France.
AFMB, Université de la Méditerranée, Parc Scientifique de LuminyMarseille Cedex 09, France.
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Protein function is encoded within the amino acid coding sequence and the variation in this sequence, and subsequent structure, provide the bases for functional diversification at the molecular and organismal levels. However, how separate protein domainscooperate to build protein activity remains largely unknown. Focusing on three domains of central Hox transcription factors, we mutagenized combinations of their domains to investigate their intrinsic functional organization. Our results demonstrate a high degree of domain interactivity, with an orchestrating role of a structurally plastic C-terminal extension of the homeodomain (HD). This domain provides, in a folding dependant manner, a topologically constrained contact with the Hox cofactor Extradenticle, which impacts the positioning of the recognition helix in the major groove of DNA. These findings provide novel insights in HD/DNA target recognition and, given the phylogeny of this C-terminal extension, also shed light on the molecular bases underlying the functional diversification of paralogous Hox families.

National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-63627OAI: oai:DiVA.org:liu-63627DiVA: diva2:381772
Available from: 2010-12-28 Created: 2010-12-28 Last updated: 2016-11-30
In thesis
1. Specification of unique neuronal sub-types by integration of positional and temporal cues
Open this publication in new window or tab >>Specification of unique neuronal sub-types by integration of positional and temporal cues
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The nervous system contains vast numbers of neuronal sub-types, generated at specific time points, in the proper location, and in proper numbers. One of the fundamental issues in neurobiology is to understand the molecular genetic mechanisms that underlie the generation of this daunting neuronal diversity.

To help shed light upon these fundamental questions, my PhD project has addressed the generation and specification of a certain group of neurons, the Ap cluster. This group of four neurons is found only in thoracic segments within the Drosophila melanogaster central nervous system, and consists of three different cell types. Mapping of the neuroblast (stem cell) that generates the Ap cluster neurons, neuroblast 5-6, and the highly restricted appearance of this cluster allowed me to address the following questions: How does NB 5-6 change its temporal competence over time to generate the Ap cluster neurons late in the lineage, and how is temporal competence altered to ensure diversity among the Ap neurons? What are the mechanisms that allow these Ap cluster neurons to emerge only in the thoracic segments?

My studies have helped identify a number of mechanisms acting to specify the Ap cluster neurons. One type of mechanism involves several of different feed-forward loops that play out during NB 5-6 lineage development. These are triggered within the stem cell, where the temporal gene castor activates a number of genes. These castor targets are subsequently involved in several regulatory feed-forward loops, that ultimately result in the unique combinatorial expression of cell fate determinants in the different Ap neurons, which in turn ultimately lead to the activation of unique terminal differentiation genes. In addition, I have identified three different mechanisms by which the NB 5-6 lineage is modulated along the neuroaxis. In the abdomen I find that an early cell cycle exit is initiated by the Bx-C gene members and Pbx/Meis cofactors, which result in the truncation of the NB 5-6 lineage, preventing the Ap cluster neurons from being generated. In thoracic segments Hox, Pbx/Meisand temporal genes act in concert to specify Ap cluster neurons, by integrating with the castor temporal gene. In anterior segments, improper Hox and temporal coding results in a failure to specify bona fide Ap cluster neurons, even though equivalents of Ap cluster neurons are generated.

In summary, my thesis work has helped identify a number of mechanisms acting to specify this unique neuronal sub-type, including: feed-forward combinatorial coding, opposing feed-forward loops and integrated temporal/Hox mediated specification throughout different axial levels. I suggest that these mechanisms may be widely used within the animal kingdom, hence contributing to the great cellular diversity observed within the central nervous system of most animal species.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2010. 102 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1211
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-63628 (URN)978-91-7393-306-3 (ISBN)
Public defence
2010-12-03, Linden, Universitetssjukhuset, Campus US, Linköpings universitet, Linköping, 09:00 (English)
Opponent
Supervisors
Available from: 2010-12-28 Created: 2010-12-28 Last updated: 2016-11-30Bibliographically approved

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Karlsson, DanielThor, StefanOrtiz Lombardia, M.

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