Establishment and regulation of neurosensory fate

Intense work has been carried out on the mechanisms involved in the induction of the otic placode and to later events of cellular differentiation, but less is known on when and how a neural competent territory is established.

We have shown that sequential FGF signaling is required first for neural commitment and later on for neuronal differentiation.  In parallel, Notch is dispensable for the establishment of a neurogenic field but  instead regulates proneural function. For this purpose,  we are investigating the interaction of FGF signaling, Notch,SoxB1 and proneural genes in otic neural fate.

For a precise control of the number, position and differentiation of neural progenitors in the inner ear,  positive extrinsic signals promoting neurosensory development are counterbalanced with neural repressors.  Largely, repressors from the bHLH gene family control the balance between neurogenesis and undifferentiated progenitors. We are investigating the role of neural repressors and how the otic placode integrates positional cues to be correctly patterned into a neurogenic versus nonneurogenic domain.

Related Publications

Radosevic M, Robert-Moreno A, Coolen M, Bally-Cuif L, Alsina B (2011). Her9 represses neurogenic fate downstream of Tbx1 and RA signaling in the inner ear. Development 138(3):397-408.

Abelló G., Khatri S., Radosevic M., Scotting PJ. , Giráldez F., Alsina  B. (2010). Independent regulation of Sox3 and Lmx1b by FGF and BMP signaling influences the neurogenic and non-neurogenic domains in the chick otic placode. Dev Biol. 339(1):166-78.

Alsina B., Giraldez F., Pujades C. (2009).  Patterning and cell fate in ear development. Int. J. Dev. Biol. 53(8-10):1503-13.

Bell D., Streit A. , Gorospe I., Varela-Nieto. I, Alsina B., Giráldez F. (2008). Spatial and temporal segregation of auditory and vestibular neurons in the otic placode.  Dev. Biol. 322:109-120

Abelló G. and Alsina B.  (2007). Establishment of a proneural field in the inner ear. Int J Dev Biol. 51:483-93.

Abelló G., Giráldez F., Alsina B. (2007). Early regionalization of the otic placode and its regulation by the Notch signaling pathway. Mech. of Dev. 124(7-8):631-45

Neves, J., Kamaid, A., Alsina, B., Giráldez, F. (2007). Differential expression of Sox2 and Sox3 in neuronal and sensory progenitors of the developing inner ear of the chick. J. Comp. Neurol. 503(4):487-500.

Pujades, C., Alsina, B., Giráldez, F. (2006). BMP4 regulates the development of hair-cells by modulating progenitor cell survival. Dev. Biol. 292(1):55-67.

Alsina B., Abelló G. , Ulloa E., Henrique D., Pujades C., Giráldez F. (2004). FGF signaling is required for determination of otic neuroblasts in the chick embryo. Dev. Biol. 276 81):119-34

 Inner ear cis regulatory sequences and TF motifs

 

The analysis of the transcriptional regulatory sequences has provided novel information on the gene regulatory networks that operate during development. Several transcription factors (TF) work in concert to regulate gene expression and it has been shown that common signatures can be used as a motif for the identification in silico of novel genes that are co-regulated by a set of TF. Our goal is to identify the inner cis-regulatory sequences (enhancers) that operate during  development and might be implicated in human deafness by using  computational approaches and ChIP-seq tools.

 

Related publications

Robert-Moreno A., Moreno,Naranjo S.,de la Calle-Mustienes E., Gómez-Skarmeta JL, Alsina  B (2011). Characterization of New Otic Enhancers of the Pou3f4 Gene Reveal Distinct Signaling Pathway Regulation and Spatio-Temporal Patterns. PLoS One 5(12):e15907

Naranjo S, Voesenek K, de la Calle-Mustienes E, Robert-Moreno A, Kokotas H, Grigoriadou M, Economides J, Van Camp G, Hilgert N, Moreno F, Alsina B, Petersen MB, Kremer H, Gómez-Skarmeta JL. (2010). Multiple enhancers located in a 1-Mb region upstream of POU3F4 promote expression during inner ear development and may be required for hearing. Hum Genet. 128(4):411-9.

 

In vivo hair cell regeneration  

 

While nonmammalian vertebrates have the ability to reconstitute damaged hair cells by regenerative mechanisms, humans and other mammalian sepcies have lost this ability  leading to hearing loss during life. We are using the zebrafish to elucidate the signaling pathways and epigenetic changes during hair cell regeneration in order to compare them in mammalian damaged inner ear tissue. 

 

 

 

 Gene regulatory networks in inner ear

 

 Dynamical mathematical models and graphical representation of complex gene interactions have proven to be useful for understanding and integrating biological data and its perturbations in disease. In collaboration with several groups of bioinformaticians we are investigating the dynamics of the  basic gene network operating during inner ear patterning.

 

 

Related publications

López García de Lomana, A, Robert-Moreno A, Dies M, Alsina B and Villà J (in preparation). Quantitative modelling of gene interactions in the early development of vertebrate inner ear

Alsina, B, López García de Lomana, A, Villà-Freixa J., and Giráldez, F (2009). Developmental biology and mathematics: the rules of an embryo. In: Contemporary Mathematics. American Mathematical Society.