Characterization of retinal ganglion cell, horizontal cell, and amacrine cell types expressing the neurotrophic receptor tyrosine kinase Ret

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Retinas are the sensory organ for light detection and visual perception. Within the retina, the photon flux is captured by photoreceptors, and the various features of visual stimuli are computed and extracted by relay neurons called bipolar cells and interneurons called horizontal cells (HCs) and amacrine cells (ACs) (Dowling, 2012; Rodieck, 1998). Their output converges onto the dendritic arbors of about 20 distinct retinal ganglion cells (RGC) types, which are the projection sensory neurons and transmit the different features of the visual stimulus to the pertinent retinorecipient areas of the brain (Levick, 1975; Masland, 2012; Wassle, 2004). Classification criteria for RGC types include dendrite morphology, brain projections, response properties to visual stimuli, functions within the visual circuit and more recently, molecular markers (Badea, Cahill, Ecker, Hattar, & Nathans, 2009; Badea & Nathans, 2004; Baden et al., 2016; Carcieri, Jacobs, & Nirenberg, 2003; Cleland & Levick, 1974a; Coombs, van der List, Wang, & Chalupa, 2006; Farrow & Masland, 2011; Helmstaedter et al., 2013; Hong, Kim, & Sanes, 2011; Martersteck et al., 2017; Sajgo et al., 2017; S. Siegert et al., 2012; Sun, Li, & He, 2002; Volgyi, Chheda, & Bloomfield, 2009). The integration of different classification schemes and the assignment of different features to individual cell types are significantly facilitated by molecular genetic approaches that allow for the labeling and characterization of RGC subpopulations or subtypes. However, since few genetic markers perfectly overlap with individual RGC types, successful genetic approaches typically require random sparse recombination, transgenic integration effects, or combinatorial genetics involving more than one locus or combinations of genetic and viral drivers (Badea & Nathans, 2004; Badea, Wang, & Nathans, 2003; Feng et al., 2000; Madisen et al., 2015; Martersteck et al., 2017; Siegert et al., 2009; Zhu, Xu, Hauswirth, & DeVries, 2014).
Tightly connected to the characterization of neuronal cell types, is the question of how these neurons develop, differentiate, and acquire their final distinctive features. One key mechanism involves transcription factors (TFs) that regulate the developmental programs of cell fate specification. The transcriptional cascade for RGC specification involves cell fate determination genes, typically active in the still proliferating neuroblasts (Atoh7/Math5) as well as RGC determining factors, such as Isl1 and Pou4f2/Brn3b (Brown, Patel, Brzezinski, & Glaser, 2001; Gan et al., 1996; Wang et al., 2001; Wang et al., 2002). Previous work has established that three members of the Pou4f family, including Pou4f1/Brn3a, Brn3b, and Pou4f3/Brn3c, participate in a combinatorial code of RGC type specification, in collaboration with several other TFs (Badea, Cahill, et al., 2009; Badea & Nathans, 2011; Shi et al., 2013). The three Brn3 factors are expressed in partially overlapping populations of RGC types, and regulate distinct morphological and molecular features of these cells, either alone or in combination. In addition, Pou4f/Brn3 TFs are also responsible for specifying other types of projection sensory neurons, involved in somatosensation, the vestibular and auditory senses (Badea et al., 2012; Erkman et al., 1996; Erkman et al., 2000; Gan et al., 1996; Wang et al., 2002; Xiang et al., 1997; Xiang, Gao, Hasson, & Shin, 1998).
In addition to transcriptional control, the development and specification of sensory neurons requires neurotrophic support, provided in large part by ligands from target derived neurotrophins (NTs) and glial derived neurotrophic factor (GDNF) families, and their receptors. Mice carrying loss of function mutations in a variety of neurotrophins or their receptors exhibit loss of sensory neuron populations or specific types (Airaksinen & Saarma, 2002; Ernsberger, 2008; Marmigere & Ernfors, 2007). The exact role of these neurotrophic factors in RGC development, however, is relatively poorly understood.
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