MAB21L1 modulates gene expression and DNA metabolic processes in the lens placode

Mutations in human MAB21L1 cause aberrations in lens ectoderm morphogenesis and lead to congenital cerebellar, ocular, craniofacial, and genital (COFG) syndrome. Murine Mab21l1-null mutations cause severe cell-autonomous defects in lens formation leading to microphthalmia, and therefore is used as a mouse model for COFG syndrome. In this study, we investigated the early-onset, single-cell-level phenotypes of murine Mab21l1-null lens ectoderms using electron microscopy (EM) and single-cell RNA sequencing (scRNA-seq). EM and immunohistochemical analyses indicated endoplasmic reticulum stress in the 24- to 26-somite stage in Mab21l1-null lens placodes. scRNA-seq analysis revealed that 131 genes were downregulated and 148 were upregulated in Mab21l1-null lens ectoderms relative to the wild type. We successfully identified 21 lens-specific genes that were downregulated in Mab21l1-null cells including three key genes involved in lens formation: Pitx3, Maf, and Sfrp2. Moreover, gene ontology analysis of the 279 differentially expressed genes indicated enrichment in housekeeping genes associated with DNA/nucleotide metabolism prior to cell death. These findings suggest that MAB21L1 acts as a nuclear factor that modulates not only lens-specific gene expression but also DNA/nucleotide metabolic processes during lens placode formation.

Early mechanisms of whisker development: Prdm1 and its regulation in whisker development and evolutionary loss

Whiskers (vibrissae) are miniaturized organs that are designed for tactile sensing. Extremely conserved among mammals, they underwent a reduction in primates and disappeared in the human lineage. Furthermore, whiskers are highly innervated and their mechanoceptors signal to the primary somatosensory cortex, where a column of neurons called “barrel” represents each of them. This structure, known as barrel cortex, occupies a large portion of the somatosensory cortex of the rodent brain. Strikingly,Prdm1conditional knockout mice are one of the rare transgenic strains that do not develop whisker hair follicles while still displaying a pelage (Robertson et al. 2007). Here we show thatPrdm1is expressed early on during whisker development, more precisely in clusters of mesenchymal cells before placode formation. Its conditional knockout leads to the loss of expression ofBmp2, Shh, Bmp4, Krt17, Edar, Gli1though leaving the β-catenin driven first dermal signal intact. Furthermore, we prove thatPrdm1expressing cells not only act as a signaling center but also as a multipotent progenitor population contributing to the formation of the dermal papilla, dermal sheath and pericytes of the vascular sinuses of vibrissae. We confirm by genetic ablation experiments that the absence of motile vibrissae (macro vibrissae) formation reverberates on the organization of nerve wiring in the mystacial pads and organization of the barrel cortex. We prove thatLef1acts upstream ofPrdm1and identify a potential enhancer (named Leaf) that might be involved in the evolutionary process that led to the progressive reduction of snout size and vibrissae in primates.

A Potential Role for MMPs during the Formation of Non-Neurogenic Placodes

The formation of non-neurogenic placodes is critical prior to the development of several epithelial derivatives (e.g., feathers, teeth, etc.) and their development frequently involves morphogenetic proteins (or morphogens). Matrix metalloproteinases (MMPs) are important enzymes involved in extracellular matrix remodeling, and recent research has shown that the extracellular matrix (ECM) can modulate morphogen diffusion and cell behaviors. This review summarizes the known roles of MMPs during the development of non-neurogenic structures that involve a placodal stage. Specifically, we discuss feather, hair, tooth, mammary gland and lens development. This review highlights the potential critical role MMPs may play during placode formation in these systems.