Abstract
MLL1 (KMT2A) and MLL2 (KMT2B) are homologous members of the mixed-lineage leukemia (MLL) family of histone methyltransferases involved in epigenomic transcriptional regulation. Their sequence variants have been associated with neurological and psychological disorders, but little is known about their roles and mechanism of action in CNS development. Using mouse retina as a model, we previously reported MLL1’s role in retinal neurogenesis and horizontal cell maintenance. Here we determine roles of MLL2 and MLL1/MLL2 together in retinal development using conditional knockout (CKO) mice. Deleting Mll2 from Chx10+ retinal progenitors resulted in a similar phenotype as Mll1 CKO, but removal of both alleles produced much more severe deficits than each single CKO: 1-month double CKO mutants displayed null light responses in electroretinogram; thin retinal layers, including shorter photoreceptor outer segments with impaired phototransduction gene expression; and reduced numbers of M-cones, horizontal and amacrine neurons, followed by fast retinal degeneration. Despite moderately reduced progenitor cell proliferation at P0, the neurogenic capacity was largely maintained in double CKO mutants. However, upregulated apoptosis and reactive gliosis were detected during postnatal retinal development. Finally, the removal of both MLLs in fated rods produced a normal phenotype, but the CKO in M-cones impaired M-cone function and survival, indicating both cell non-autonomous and autonomous mechanisms. Altogether, our results suggest that MLL1/MLL2 play redundant roles in maintaining specific retinal neurons after cell fate specification and are essential for establishing functional neural networks.
Highlights
The mixed-lineage leukemia (MLL) family of histone lysine methyltransferases (KMTs) catalyze the methylation at lysine (K) 4 of histone H3 (Shilatifard, 2008; Crump and Milne, 2019)
Mll1 and Mll2 are ubiquitously expressed in the developing mouse retinae according to the published single-cell RNA-seq data (Clark et al, 2019) (Supplementary Figures S1A,B)
Cre excision produced a non-functional MLL1 protein lacking the nuclear targeting signals (NTS) (Gan et al, 2010) and/or a short non-functional MLL2 peptide resulted from a frameshift at exon 2 (Glaser et al, 2006) (Figure 1A)
Summary
The mixed-lineage leukemia (MLL) family of histone lysine methyltransferases (KMTs) catalyze the methylation at lysine (K) 4 of histone H3 (Shilatifard, 2008; Crump and Milne, 2019). The MLL family has six members, namely, MLL1 (KMT2A), MLL2 (KMT2B), MLL3 (KMT2C), MLL4 (KMT2D), SET1DA and SET1DB, all of which contain a conserved catalytic SET domain (Allis et al, 2007; Crump and Milne, 2019) These MLL enzymes usually form large multi-protein complexes (Yokoyama et al, 2004; Dou et al, 2006; Shinsky et al, 2015) that mediate chromatin remodeling and MLL1/MLL2 in Retina transcriptional regulation during tissue genesis (Glaser et al, 2006; Krivtsov and Armstrong, 2007; Slany, 2016; Cenik and Shilatifard, 2021). Their functions and mechanisms of action in the CNS development and neuronal disease pathogenesis remain to be elucidated
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
