Neural Development – The roles of Brn3a, Islet1, and Hmx1 transcription factors in nervous system development

 

The Turner lab has focused on the role of transcription factors in the development of peripheral sensory neurons, the spinal cord, midbrain, and habenula. Transcription factors are proteins which bind to DNA in the nucleus to switch on or off the genes which characterize specific cell types. Without the correct complement of transcription factors, cells undergo an “identity crisis” and fail to execute their correct developmental programs. Many genetic disorders in the brain and other organ systems have been linked to defective transcription factor function. Most of the Turner Lab studies have been conducted in transgenic mice in which they either “knockout” the factor of interest, or express a tracer protein in the neurons that express the factor. Studies have focused mainly on the homeodomain transcription factors Brn3a, Islet1, and Hmx1. In recent work, they have shown that without the combinatorial effects of Brn3a and Islet1, developing sensory neurons remain in a “ground state” in which they express general neuronal markers but none of the specific genes that characterize sensory function (Dykes, et al., 2011). In another study, the Turner Lab has shown that Hmx1, which is downstream of Brn3a, is essential for development of sensory neurons innervating the lateral face (Quina, et al., 2012). In the CNS, they have shown that Brn3a is also essential for development of the medial habenula, a poorly understood thalamic nucleus (Quina, et al., 2009). Remarkably, although it is essential for the development of several kinds of neurons, Brn3a appears to regulate different sets of genes in each region of the nervous system. How this flexiblity of function is generated is the subject of active research.

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Click here for movie showing optical projection tomography of the cranial sensory neurons in a Hmx1/dumbo mouse embryo (from Quina et al.,  2012) .

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Click here for movie  showing optical projection tomography imaging of E12.5 Brn3a/Islet1 DKO and control embryos.  Embryos were harvested at E12.5, genotyped, fixed, LacZ-stained and cleared for OPT.  OPT was used to generate 400 rotational images of each embryo, and 200 such images, representing 180 degrees of rotation, were used to produce the video files.   OPT was performed using a Bioptonics 3100M scanner at the Seattle Childrens/UW SANTA imaging facility, Dr. Tim Cox, director.

Arrowheads in  indicate the foreshortened dorsal roots observed in the DKO embryo.  Legend in order of appearance:  CPx, cervical plexus; BPx, brachial plexus; HB, hindbrain; SC, spinal cord; DRG, dorsal root ganglia; TG, trigeminal ganglion; Mn, mandibular branch, trigeminal system; Mx, maxillary branch, trigeminal system (infraorbital nerve); 8g, vestibulocochlear ganglion; 9g, superior ganglion.

Reference:  Dykes, I. M., Tempest, L., Lee, S. I. and Turner, E. E. (2011). Brn3a and islet1 act epistatically to regulate the gene expression program of sensory differentiation. J Neurosci 31, 9789-99.