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Background: The molecular pathogenesis of atopic dermatitis (AD), presenting skin barrier dysfunction and abnormal inflammations around 1–2 months, is unreported. Objective: We aimed to examine the molecular pathogenesis of very early‐onset AD by skin surface lipid‐RNA (SSL‐RNA) using a non‐invasive technology in infants aged 1 and 2 months from a prospective cohort. Methods: We collected sebum by oil‐blotting film of infants aged 1 and 2 months and analysed RNAs in their sebum. We diagnosed AD according to the United Kingdom Working Party's criteria. Results: Infants with AD aged 1 month showed lower expression of genes related to various lipid metabolism and synthesis, antimicrobial peptides, tight junctions, desmosomes and keratinization. They also had higher expression of several genes involved in Th2‐, Th17‐ and Th22‐type immune responses and lower expression of negative regulators of inflammation. In addition, gene expressions related to innate immunity were higher in AD infants. Infants aged 1 month with neonatal acne and diagnosed with AD aged 2 months already had gene expression patterns similar to AD aged 1 month in terms of redox, lipid synthesis, metabolism and barrier‐related gene expression. Conclusion: We identified molecular changes in barrier function and inflammatory markers that characterize the pathophysiology of AD in infants aged 1 month. We also revealed that neonatal acne at 1 month could predict the subsequent development of AD by sebum transcriptome data. [ABSTRACT FROM AUTHOR]

Distinct classes of SOX10 mutations result in peripheral demyelinating neuropathy, central dysmyelinating leukodystrophy, Waardenburg syndrome, and Hirschsprung disease, collectively known as PCWH. Meanwhile, SOX10 haploinsufficiency caused by allelic loss-of-function mutations leads to a milder non-neurological disorder, Waardenburg–Hirschsprung disease. The cellular pathogenesis of more complex PCWH phenotypes in vivo has not been thoroughly understood. To determine the pathogenesis of PCWH, we have established a transgenic mouse model. A known PCWH-causing SOX10 mutation, c.1400del12, was introduced into mouse Sox10-expressing cells by means of bacterial artificial chromosome (BAC) transgenesis. By crossing the multiple transgenic lines, we examined the effects produced by various copy numbers of the mutant transgene. Within the nervous systems, transgenic mice revealed a delay in the incorporation of Schwann cells in the sciatic nerve and the terminal differentiation of oligodendrocytes in the spinal cord. Transgenic mice also showed defects in melanocytes presenting as neurosensory deafness and abnormal skin pigmentation, and a loss of the enteric nervous system. Phenotypes in each lineage were more severe in mice carrying higher copy numbers, suggesting a gene dosage effect for mutant SOX10 . By uncoupling the effects of gain-of-function and haploinsufficiency in vivo, we have demonstrated that the effect of a PCWH-causing SOX10 mutation is solely pathogenic in each SOX10-expressing cellular lineage in a dosage-dependent manner. In both the peripheral and central nervous systems, the primary consequence of SOX10 mutations is hypomyelination. The complex neurological phenotypes in PCWH patients likely result from a combination of haploinsufficiency and additive dominant effect. [ABSTRACT FROM AUTHOR]

Summary: Neural circuits consist of highly precise connections among specific types of neurons that serve a common functional goal. How neurons distinguish among different synaptic targets to form functionally precise circuits remains largely unknown. Here, we show that during development, the adhesion molecule cadherin-6 (Cdh6) is expressed by a subset of retinal ganglion cells (RGCs) and also by their targets in the brain. All of the Cdh6-expressing retinorecipient nuclei mediate non-image-forming visual functions. A screen of mice expressing GFP in specific subsets of RGCs revealed that Cdh3-RGCs which also express Cdh6 selectively innervate Cdh6-expressing retinorecipient targets. Moreover, in Cdh6-deficient mice, the axons of Cdh3-RGCs fail to properly innervate their targets and instead project to other visual nuclei. These findings provide functional evidence that classical cadherins promote mammalian CNS circuit development by ensuring that axons of specific cell types connect to their appropriate synaptic targets. [ABSTRACT FROM AUTHOR]

Abstract: A brain-derived neurotrophic factor (BDNF) receptor TrkB involves three spliced variants, namely the tyrosine kinase domain (TK) intact (+) and two TK(−) isoforms T1 and T2, yet their precise roles are largely unknown. Here we extensively map the mRNA expression patterns of BDNF and TrkB variants, further to gain insights in TK(−) specific functions during mouse development. Consequently, we found that TK(+), T1 and T2 were expressed in distinct regions of the mouse nervous system at the embryonic and postnatal stages, implicating separable functions of TK(−) forms. Additionally we uncovered five expressed segments in the intron between T2 and T1 specific exons, and one of these segments was revealed to code novel TK(−) receptors with unique responsiveness in vitro. These results suggest dynamic modes of expression from the Ntrk2 gene locus and multiple roles of TK(−) forms in the developing mouse nervous system. [Copyright &y& Elsevier]