PgmNr M5062: Hox proteins are essential for motor neuron subtype differentiation and connectivity by regulating the expression of Ret/Gfra genes.

Authors:
C. Catela 1 ; M. M. Shin 1 ; D. H. Lee 1 ; J. P. Liu 2 ; J. S. Dasen 1


Institutes
1) NYU School of Medicine, New York, NY; 2) University of Virginia School of Medicine, Charlottesville, VA.


Abstract:

Precise regulation of gene expression is fundamental for the generation of neuronal diversity and circuit assembly during development. However, the transcriptional mechanisms that establish patterns and levels of gene expression in a given neuronal population remain largely elusive. Here we show that HOX/HOX cofactor interactions in motor neuron (MN) subtypes are essential for their specification and connectivity through regulation of the expression of Ret/Gfra surface receptors, essential for MN organization, axon branching and guidance. HOX and MEIS transcription factors control the levels of Ret and define the expression pattern of Gfra1 and Gfra3 in MN subtypes. Deletion of Ret and Gfra3 in mice results in MN organization and innervation defects similar to those observed in HOX mutants. Finally, ectopic expression of Ret and Gfra1 is sufficient to cause MNs to respond to limb derived signals, circumventing the necessity for Hox genes. These results show that one of the strategies of Hox genes is to regulate the levels and expression pattern of cell surface receptors, gating the ability of MNs to respond to limb signals. Future experiments will aim to uncover the full spectrum of effector genes downstream of HOX networks, providing novel insights into the transcriptional strategies employed by Hox proteins during MN subtype development.