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Deciphering new Hox gene functions in the postnatal and adult brain

Hox genes encode DNA binding proteins, also called transcription factors, which bind to a specific sequence of genomic DNA by a binding domain called the homeodomain. They act as transcriptional regulators controlling the expression and production of other genes and proteins. In mammals, Hox gene functions have been mostly studied at embryonic stages where they play key roles in determining neuronal organization within the hindbrain and spinal cord, notably in specifying neuronal cell types. However, we recently showed that Hox genes are also active in the brain after birth.
The main objective our group is to understand why HOX proteins are still present in the brain after birth, and if they contribute to cerebral processes that occur at those stages, such as the maturation of neuronal circuitry. As there are 39 Hox genes in mammals, we selected one of these genes as a model to investigate Hox functions after birth: the Hoxa5 gene.

Mutant mouse models for Hox gene inactivation
Our strategy is to inactivate the gene and to evaluate how the loss of function can affect brain function and animal behavior and thus to understand the function of this gene/protein in the brain after birth. Due to the complexity of the mammalian brain, there are currently no alternatives to animal that would allow answering our questions, notably to evaluate the impact on mouse behaviour. We thus developed a mouse model in which we induced the inactivation of the Hoxa5 gene just after birth (Figure 1).

Identification of HOX functions in the postnatal brain: characterization of Hox cKO mutant mice
Using this mouse model, we investigate the functional consequences of Hoxa5 gene inactivation in the postnatal brain. The brain is analysed by histology, while the behaviour of mutant mice is analysed using different tests allowing to evaluate their motor activity and coordination, their balance, their procedural memory… As HOX proteins regulate the expression of other genes, we also identified by gene expression profiling what genes are modified when HOXA5 is absent in the brain. This should help to identify the processes that are modulated by HOXA5. Culture of isolated neurons can next be used to study these processes in a simplified model (Figure 2).
 


 

Understanding Hox proteins mode of action: identification of target genes and interacting proteins
HOX proteins are not working alone; they are part of a network of interacting proteins that can help them in their functions, notably to select and to bind the DNA at the appropriate sequence. Using multi-facetted molecular approaches we aim to determine the DNA sequences bound by HOXA5 and to identify its interacting proteins.