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Hedgehog-Dependent E3-Ligase Midline1 Regulates Ubiquitin-Mediated Proteasomal Degradation of Pax6 During Visual System Development

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Hedgehog-Dependent E3-Ligase Midline1 Regulates Ubiquitin-Mediated Proteasomal Degradation of Pax6 During Visual System Development Hedgehog-dependent E3-ligase Midline1 regulates ubiquitin-mediated proteasomal degradation of Pax6 during visual system development Thorsten Pfirrmanna,1, Enrico Jandta,1, Swantje Ranfta,b, Ashwin Lokapallya, Herbert Neuhausa, Muriel Perronc, and Thomas Hollemanna,2 aInstitute for Physiological Chemistry, University of Halle-Wittenberg, 06114 Halle, Germany; bGynecological Hospital, University Medical Center Mannheim, 68167 Mannheim, Germany; and cParis-Saclay Institute of Neuroscience, CNRS, Univ Paris Sud, Université Paris-Saclay, 91405 Orsay, France Edited by Richard M. Harland, University of California, Berkeley, CA, and approved July 19, 2016 (received for review January 16, 2016) Pax6 is a key transcription factor involved in eye, brain, and pancreas remains unclear how Pax6 protein is removed from the eyestalk development. Although pax6 is expressed in the whole prospective territory on time. Some authors report the regulation of Pax6 retinal field, subsequently its expression becomes restricted to the activity by posttranslational modifications (21–23), and most optic cup by reciprocal transcriptional repression of pax6 and pax2. interestingly, Tuoc et al. showed that in cortical progenitor cells, However, it remains unclear how Pax6 protein is removed from the Pax6 protein is degraded by the proteasome mediated by Trim11 eyestalk territory on time. Here, we report that Mid1, a member of (24). However, the existence of similar mechanisms leading to the RBCC/TRIM E3 ligase family, which was first identified in patients the development of the visual system is not known. with the X-chromosome–linked Opitz BBB/G (OS) syndrome, inter- The data of our present study show that Midline1 (Mid1) acts with Pax6. We found that the forming eyestalk is a major do- serves as one of these links. MID1, a member of the RBCC/ main of mid1 expression, controlled by the morphogen Sonic TRIM E3 ligase family, was first identified in patients with the hedgehog (Shh). Here, Mid1 regulates the ubiquitination and protea- X-chromosome–linked Opitz BBB/G (OS) syndrome. Patients somal degradation of Pax6 protein. Accordantly, when Mid1 levels suffer from multiple malformations of the ventral midline as a are knocked down, Pax6 expression is expanded and eyes are enlarged. consequence of mutations in the MID1 gene (25, 26). In previous Our findings indicate that remaining or misaddressed Pax6 protein is studies, Mid1 has been described to regulate protein phospha- cleared from the eyestalk region to properly set the border between tase 2A (PP2A) stability (27–30). PP2A/α4 is not the only known the eyestalk territory and the retina via Mid1. Thus, we identified a substrate, because recently it was shown that Mid1 interacts with posttranslational mechanism, regulated by Sonic hedgehog, which is the GLI regulator Fu, leading to a cytoplasmic retention of GLI3 important to suppress Pax6 activity and thus breaks pax6 autoregu- in cancer cells (31). We show that Mid1 can physically interact lation at defined steps during the formation of the visual system. with Pax6 leading to the ubiquitination and proteasomal degra- dation of Pax6 protein. We observe an overlapping expression of Xenopus | mid1 | pax6 | eye development | ubiquitin mid1 and pax6 in early stages of Xenopus development. In tad- pole stages, mid1 transcripts are concentrated in the optic stalk ax6 is an evolutionary highly conserved transcription factor, territory in contrast to pax6. Overexpression of shh strongly in- Pplaying key roles as a potent cell fate determinant in the duces mid1, whose expression expands to the whole remaining development of the eye, brain, and pancreas (1–4). Pax6 is a eye vesicle. Accordingly, when Mid1 levels are knocked down, Pax6 member of the PAX family of transcription factors (5, 6). Pax6 expression is expanded, and eyes are enlarged. Taken together, we autoregulation was suggested based on mouse genetic experi- ments (7) and studies regarding the quail, as well as human, Significance promoters (8, 9). Thus, to maintain pax6 expression, Pax6 pro- tein is required, which has been assumed already from studies of The first morphological sign of vertebrate eye formation is the the Small eye (SEY) mutant mice (10, 11). In humans, hetero- appearance of eye vesicles on both sides of the ventral di- zygous mutations in PAX6 cause a wide variety of ocular defects, encephalon, which primarily originate from a uniform Pax6- whereas the homozygous loss results in anophthalmia (12). Not positive eye field. A key regulator for this process, which co- only does the reduction of Pax6 protein levels cause severe de- incides with the establishment of the proximo-distal axis of the velopmental defects in the eye, but transgenic mice carrying eye with eyestalk and retina, is the morphogen Shh. Shh in- multiple copies of the human PAX6 gene also have similar ocular duces the expression of pax2, which represses pax6 in the abnormalities as the small eye mice (13, 14). Moreover, in presumptive eyestalk region. Here, we report on the identifi- Drosophila and in vertebrates like Xenopus, overexpression of cation of the E3-ligase Mid1, which is induced by Shh and pax6 is able to induce the formation of ectopic eyes (15, 16). As a targets transcription factor Pax6 for proteasomal degradation. whole, Pax6 is one of the most important regulators of eye de- Our findings might provide insight into a mechanism, in which velopment and its function is critically dependent on a tempo- a morphogen initiates the degradation of a transcription factor rarily and quantitatively defined expression level (4). to form sharp boundaries of gene expression. In Xenopus, pax6 can be detected in all neuroblasts of the BIOLOGY developing retina soon after gastrulation. In early tailbud stages, Author contributions: M.P. and T.H. designed research; T.P., E.J., S.R., A.L., H.N., M.P., and DEVELOPMENTAL pax6 is expressed homogenously in all parts of the optic vesicle. T.H. performed research; T.P., E.J., and H.N. contributed new reagents/analytic tools; T.H. In tadpoles, pax6 is limited to the lens epithelium and later to analyzed data; and T.H. wrote the paper. cells of the inner nuclear layer and the ganglion cell layer. The authors declare no conflict of interest. However, pax6 transcripts are barely detectable in the outer This article is a PNAS Direct Submission. nuclear layer containing photoreceptor cells but clearly visible in 1T.P. and E.J. contributed equally to this work. the ciliary marginal zone (17, 18). On the one hand, the sharp 2To whom correspondence should be addressed. Email: [email protected] boundary between the optic cup with pax6 and the optic stalk halle.de. region with pax2 is established by reciprocal transcriptional re- This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. pression of these two pax genes (19, 20). On the other hand, it 1073/pnas.1600770113/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1600770113 PNAS | September 6, 2016 | vol. 113 | no. 36 | 10103–10108 Downloaded by guest on October 4, 2021 provide evidence that Pax6 is a substrate for Mid1 and insights into single cell of two-cell stage embryos and examined mid1 ex- how remaining or misaddressed Pax6 protein is cleared from the pression at tadpole stage. Misexpression of shh resulted in an up- eyestalk region to properly set the border between the eyestalk regulation of the known target, the hh receptor ptc1 (Fig. 1 B, d–d′ territory and the retina at the right time. and Fig. S1B,nptc1= 20/27; nctrl = 6/60; P = 1.42E-11) in neural ectoderm. Moreover, mid1 expression was strongly induced but Results restricted to the optic cup (Fig. 1 B, a–a′;nmid1= 66/81; nctrl = Mid1 Expression in Cells of the Forming Optic Stalk Is Under the 3/44; P = 1.08E-15) similar to pax2 (Fig. 1 B, b–b′;npax2= 74/83; Control of Shh. We analyzed the expression of mid1 during Xen- nctrl = 3/42; P = 4.21E-18), whereas pax6 was repressed on shh opus laevis development by whole mount in situ hybridizations RNA injection (Fig. 1 B, c–c′;npax6= 86/106; nctrl = 4/51; P = (Wmish) on embryos of Nieuwkoop and Faber (NF) stage 24–38 3.47E-18) (33). Interestingly, Hh-dependent regulation of mid1 is (Fig. 1A). While confirming the pattern described by Suzuki not mediated by pax2 because suppression of pax2 function did not – ′ et al. (32), a closer look revealed that mid1 is expressed early in impair mid1 expression (Fig. 1 B, e e ; 8/11 eyes analyzed in sec- tion) but resulted in an enlargement of the retina and ectopic pax6 the whole eye vesicle. From the NF stage 32 onward, high levels – ′ of mid1 transcripts were detected in the ventral part of the expression in the eye vesicle (Fig. 1B, f f ; 13/16 eyes analyzed in pax2 pax6 forming eye and especially within the forming optic stalk (Fig. 1 section). Moreover, is under the control of ,because suppression of pax6 ledtoanexpansionofpax2 expression into the A, c4–c7 and d1–d3). Here, the expression of mid1 appears remaining eye vesicle (Fig. 1 B, g–g″; npax2 = 7/17; nctrl = 4/47; P = similar, although not identical to those described for transcrip- 1.45E-08) and pax2 RNA injection impaired pax6 expression as in tion factors vax1 or pax2, known targets of the hedgehog (hh) mice (Fig. 1 B, h–h″ and Fig. S1C; npax6 = 9/35; nctrl = 4/47; P = pathway (Fig. S1A) (33). To analyze whether Hedgehog also 1.5E-14) (20). Because Mid1 is an E3 ubiquitin ligase, we assume regulates mid1 expression, we injected synthetic shh RNA into a that Mid1 regulates Pax6 expression on a posttranslational level rather than on a transcriptional level like Pax2. Mid1 Interacts with Pax6.
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