Conserved regulation of Math5 and Math1 revealed by Math5-GFP transgenes

Abstract

Retinal ganglion cell genesis requires the proneural bHLH transcription factor Math5 (Atoh7), but little is known about the regulatory elements that control its expression. Here, we investigate Math5 gene regulation using transgenic mice. These mice express GFP in the prenatal retina, livelabeling RGC axon migration and innervation of the brain. Unexpectedly, these Math5-GFP transgenes are also found in Math1 expression domains throughout the nervous system, intriguing since Math5 and Math1 normally exhibit nonoverlapping expression. Furthermore, Math5-GFP and Math1 are regulated similarly, by both Pax6 and Math1 itself, in the lower rhombic lip and dorsal spinal cord. We also show that Pax6 binds to particular Math5 and Math1 regulatory sequences in vitro. Together these data suggest that these atonal semi-orthologues may share conserved regulatory elements that are normally silent in the Math5 gene.

Notch signaling differentially regulatesAtoh7andNeurog2in the distal mouse retina

“…An excellent example is Drosophila atonal (ato), which encodes a bHLH protein that is highly related to the mammalian Atoh, Neurog and Neurod protein families (Hassan and Bellen, 2000;Bertrand et al, 2002). The ato semi-orthologues Atoh7 and Atoh1 are expressed in mutually exclusive regions of the mouse nervous system, subdividing ato sensory functions within the mammalian visual (Atoh7), auditory (both genes) and proprioceptive (Atoh1) systems (Jarman et al, 1993(Jarman et al, , 1995Helms et al, 2000;Hufnagel et al, 2007;Saul et al, 2008). Moreover, ato functions in the fly eye are further subdivided between mouse Atoh7 and Neurog2 (Hufnagel et al, 2010).…”

“…Intriguingly, these two modes of regulation are temporally separated by the onset of ato autoregulation within the furrow. In the mouse eye, neither mouse Atoh7 nor Neurog2 autoregulates their expression (Brown et al, 2001;Wang et al, 2001;Hutcheson et al, 2005;Kele et al, 2006;Hufnagel et al, 2007Hufnagel et al, , 2010Riesenberg et al, 2009a), but Neurog2 appears first along the advancing retinal wavefront, and directly activates Atoh7 transcription (Skowronska-Krawczyk et al, 2009;Hufnagel et al, 2010). Thus, Neurog2 crossregulation of Atoh7 is correlated with progression of neurogenesis.…”

Identification of Novel Regulators of atonal Expression in the Developing Drosophila Retina

“…Of further interest, patients with CHARGE syndrome also display eye and ear abnormalities, including coloboma, a symptom that is also attributed to mutations in the mammalian homolog of the hedgehog gene (Schimmenti et al 2003;Fuerst et al 2007). The human homolog of atonal (math5) is expressed and critically required for both proper retinal and auditory development (Brown et al 1998Wang et al 2001;Yang et al 2003;Le et al 2006;Hufnagel et al 2007;Saul et al 2008) and thus may be a good candidate for a critical target gene that is disrupted in CHARGE syndrome.…”

Eye-specific expression of an ancestral jellyfish PaxB gene interferes with Pax6 function despite its conserved Pax6/Pax2 characteristics

“…Distinct members of the basic helix-loop-helix (bHLH) family of transcription factors specify the cell fate within a developing mouse retina (Livesey and Cepko, 2001). With respect to the present study it is noteworthy that Pax6 directly regulates genes encoding Ngn2, Mash1 and Math5 (Marquardt et al, 2001;Hufnagel et al, 2007). For RGC formation both Math5 and Pax6 are required (Brown et al, 2001;Marquardt et al, 2001;Wang et al, 2001;Hutcheson et al, 2005;Mu et al, 2005).…”