MLL1 is essential for retinal neurogenesis and horizontal inner neuron integrity

Diana S Brightman,Rachel L Grant,Shiming Chen,Anne K Hennig,Philip A Ruzycki,Ray Suzuki

doi:10.1038/s41598-018-30355-3

Abstract

Development of retinal structure and function is controlled by cell type-specific transcription factors and widely expressed co-regulators. The latter includes the mixed-lineage leukemia (MLL) family of histone methyltransferases that catalyze histone H3 lysine 4 di- and tri-methylation associated with gene activation. One such member, MLL1, is widely expressed in the central nervous system including the retina. However, its role in retinal development is unknown. To address this question, we knocked out Mll1 in mouse retinal progenitors, and discovered that MLL1 plays multiple roles in retinal development by regulating progenitor cell proliferation, cell type composition and neuron-glia balance, maintenance of horizontal neurons, and formation of functional synapses between neuronal layers required for visual signal transmission and processing. Altogether, our results suggest that MLL1 is indispensable for retinal neurogenesis and function development, providing a new paradigm for cell type-specific roles of known histone modifying enzymes during CNS tissue development.

Highlights

The vertebrate retina is a central nervous system structure specialized for vision
Consistent with Quantitative real-time PCR (qRT-PCR) results (Fig. 1B), the In situ hybridization (ISH) signal intensity was much higher at P14 compared to P7 and earlier, in the inner nuclear layer (INL) and ganglion cell layer (GCL) (Fig. 1H,G)
Conditional knockout of MLL1 in developing retinas resulted in significant reductions of retina thickness, detected as early as Postnatal day 0 (P0)

Summary

Introduction

The vertebrate retina is a central nervous system structure specialized for vision. Six major classes of neurons and one type of glia (Muller) are organized into three cell layers[1]. The inner nuclear layer (INL) contains cell bodies of Muller glia and bipolar, horizontal and amacrine interneurons, which mediate transmission and initial processing of the visual signal. Retinogenesis is governed by a genetic program that integrates extrinsic signals to precisely control spatial and temporal patterning of the retina[4,5] This genetic program is built on a network of lineage-specific transcription factors (TF), many of which are multifunctional and act at specific developmental time points. Lineage-specific transcription factors interact with widely-expressed co-regulators to modulate chromatin accessibility for target gene regulation These co-regulators include enzymes that catalyze post-translational modifications of histone tails (“histone marks”). All contain the conserved catalytic SET domain and form large multi-protein complexes to remodel the epigenome[19,20,21] Discovered through their association with cancer[22,23], MLLs are essential for organ/ tissue genesis. Targeted inactivation of MLL family members in various cell types has revealed diverse roles in developing[27,28,29,30,31,32,33] and adult animals[21]

Methods

Results

Conclusion