MYT1L in the making: emerging insights on functions of a neurodevelopmental disorder gene

Abstract

Large scale human genetic studies have shown that loss of function (LoF) mutations in MYT1L are implicated in neurodevelopmental disorders (NDDs). Here, we provide an overview of the growing number of published MYT1L patient cases, and summarize prior studies in cells, zebrafish, and mice, both to understand MYT1L's molecular and cellular role during brain development and consider how its dysfunction can lead to NDDs. We integrate the conclusions from these studies and highlight conflicting findings to reassess the current model of the role of MYT1L as a transcriptional activator and/or repressor based on the biological context. Finally, we highlight additional functional studies that are needed to understand the molecular mechanisms underlying pathophysiology and propose key questions to guide future preclinical studies.

Fig. 1. Schematic of human MYT1L domains and predicted protein structure by AlphaFold.

A Distribution of missense mutations described in clinical studies (top, red) compared to a general population sample (gnomAD, bottom, with gray bars displaying all missense mutations and black bars displaying ‘possible damaging mutations’ as predicted by PolyPhen2). ‘Possible damaging mutations’ in the general population are largely excluded from the regions mutated in clinical samples. B AlphaFold’s calculated confidence measure (pLDDT score) per-residue of the model’s prediction based on the IDDT-Cα metric. C 3D AlphaFold structure (AF-Q9UL68-F1) prediction of MYT1L protein showing the N-terminal domain (magenta), MYT1 domain (orange), coiled domain (yellow), and six zinc finger domains (blue) coming in proximity with each other to form a putative DNA-binding pocket. Unannotated regions are shown in green. (https://alphafold.ebi.ac.uk/entry/Q9UL68). D Loss of function mutations from patient reports are found throughout the protein. Those not within the annotated zinc finger domains (blue) are shown in red. E Isolated and magnified view of the zinc finger domains (blue) shows patient mutations (cyan) cluster in the zinc fingers.

Fig. 2. Mouse embryonic brain expression patterns of MYT family transcription factors.

A Quantitative RT-PCR summarized as relative mRNA expression of Myt1 (red), Myt1l (blue), and Myt3 (green) in the developing mouse from E10.5 to adult, adapted from [13]. B Color coded summary of published in situ hybridization data from Matsushita et al. [13] showing the spatial expression pattern of MYT1, MYT1L, and MYT3 in the developing cortex. C The diagram shows a hypothesized mechanism of microcephaly in Myt1l mutant mice at E14. APa, archipallium; BG, basal ganglia; CTX, cortex; DTe, dorsal telencephalon; fIC, fibers of the internal capsule; HC, hippocampus; HT, hypothalamus; IC, internal capsule; LGE, lateral ganglionic eminence; MGE, medial ganglionic eminence; OpV, optic vesicle; Pal, pallidum; POA, preoptic area; Str, striatum; TH, thalamus; Vg, trigeminal ganglion; VTe, ventral telencephalon.

Fig. 3. Speculative “ready-set-go” model of MYT TFs during neuronal differentiation.

A “Ready” phase: initial expression of MYT1 during early neurodevelopment represses non-neuronal and neuronal maturation gene expression programs. B “Set” phase: MYT1 expression fades and is replaced by MYT1L and is still net repressive to prevent maturation gene expression. This ensures maintenance of the progenitor pool. C “Go” phase: MYT1L, due to possible interactions with cofactors, postransciptional modifications, or increased expression levels activates the expression of neuronal maturation genes. Figure created with BioRender.com.