Wenjuan Zhu

All Publications

• KCTD1/KCTD15 complexes control ectodermal and neural crest cell functions and their impairment causes aplasia cutis. The Journal of clinical investigation Raymundo, J. R., Zhang, H., Smaldone, G., Zhu, W., Daly, K. E., Glennon, B. J., Pecoraro, G., Salvatore, M., Devine, W. A., Lo, C. W., Vitagliano, L., Marneros, A. G. 2023

  Abstract

  Aplasia cutis congenita (ACC) is a congenital epidermal defect of the midline scalp and has been proposed to be due to a primary keratinocyte abnormality. Why it forms mainly at this anatomic site has remained a longstanding enigma. KCTD1 mutations cause ACC, ectodermal abnormalities, and kidney fibrosis, whereas KCTD15 mutations cause ACC and cardiac outflow tract abnormalities. Here, we find that KCTD1 and KCTD15 can form multimeric complexes and can compensate for each other's loss, and that disease mutations are dominant-negative, resulting in lack of KCTD1/KCTD15 function. We demonstrate that KCTD15 is critical for cardiac outflow tract development, whereas KCTD1 regulates distal nephron function. Combined inactivation of KCTD1/KCTD15 in keratinocytes results in abnormal skin appendages, but not in ACC. Instead, KCTD1/KCTD15 inactivation in neural crest cells results in ACC linked to midline skull defects, demonstrating that ACC is not caused by a primary defect in keratinocytes but is a secondary consequence of impaired cranial neural crest cells giving rise to midline cranial suture cells that express keratinocyte-promoting growth factors. Our findings explain the clinical observations in patients with KCTD1 versus KCTD15 mutations, establish KCTD1/KCTD15 as critical regulators of ectodermal and neural crest cell functions, and define ACC as a neurocristopathy.

  View details for DOI 10.1172/JCI174138

  View details for PubMedID 38113115

• AP-2α/AP-2β transcription factors are key regulators of epidermal homeostasis. bioRxiv : the preprint server for biology Zhang, H., Raymundo, J., Daly, K. E., Zhu, W., Senapati, B., Marneros, A. G. 2023

  Abstract

  AP-2 transcription factors regulate ectodermal development but their roles for epidermal homeostasis in the adult skin are unknown. We find that AP-2α is the predominant AP-2 family member in adult epidermis, followed by AP-2β. Through inactivation of AP-2α, AP-2β, or both in keratinocytes we assessed the effects of a gradient of epidermal AP-2 activity on skin function. We find that (1) loss of AP-2β in keratinocytes is compensated for by AP-2α, (2) loss of AP-2α impairs terminal keratinocyte differentiation and hair morphogenesis, and (3) the combined loss of AP-2α/AP-2β results in more severe skin and hair abnormalities. Keratinocyte differentiation defects precede a progressive neutrophilic skin inflammation. Inducible inactivation of AP-2α/AP-2β in the adult phenocopies these manifestations. Transcriptomic analyses of epidermis lacking AP-2α or AP-2α/AP-2β in keratinocytes demonstrate a terminal keratinocyte differentiation defect with upregulation of alarmin keratins and of several immune pathway regulators. Moreover, our analyses suggest a key role of loss of AP-2α-dependent gene expression of CXCL14 and KRT15 as an early pathogenic event towards the manifestation of skin inflammation. Thus, AP-2α/AP-2β are critical regulators of epidermal homeostasis in the adult skin.

  View details for DOI 10.1101/2023.12.03.569763

  View details for PubMedID 38105942

  View details for PubMedCentralID PMC10723278

• Generation of two induced pluripotent stem cell lines from patients with Down syndrome. Stem cell research Zhu, W., Liu, W., Yu, R., Manning, M., Waran Romfh, A., Wu, J. C. 2023; 72: 103204

  Abstract

  Down syndrome (DS) is caused by trisomy of Homo sapiens chromosome 21 (HSA21) and is by far the most common chromosomal disorder accompanied by neurodevelopmental disorders and congenital heart disease. Here, we generated two induced pluripotent stem cell (iPSC) lines from two patients with DS. These two lines exhibited normal morphology, trisomy 21 karyotype, pluripotency and differentiation capability into derivatives of three germ layers. The patient-specific iPSC lines arean invaluable resource in research to model DS-related cellular and molecular pathologies and test possible therapeutic strategies for DS.

  View details for DOI 10.1016/j.scr.2023.103204

  View details for PubMedID 37734318

• Contribution of LRP1 in Human Congenital Heart Disease Correlates with Its Roles in the Outflow Tract and Atrioventricular Cushion Development GENES Arrigo, A. B., Zhu, W., Williams, K. A., Guzman-Moreno, C., Lo, C., Lin, J. I. 2023; 14 (4)

  Abstract

  Due to the prevalence of congenital heart disease in the human population, determining the role of variants in congenital heart disease (CHD) can give a better understanding of the cause of the disorder. A homozygous missense mutation in the LDL receptor-related protein 1 (Lrp1) in mice was shown to cause congenital heart defects, including atrioventricular septal defect (AVSD) and double outlet right ventricle (DORV). Integrative analysis of publicly available single-cell RNA sequencing (scRNA-seq) datasets and spatial transcriptomics of human and mouse hearts indicated that LRP1 is predominantly expressed in mesenchymal cells and mainly located in the developing outflow tract and atrioventricular cushion. Gene burden analysis of 1922 CHD individuals versus 2602 controls with whole-exome sequencing showed a significant excess of rare damaging LRP1 mutations in CHD (odds ratio (OR) = 2.22, p = 1.92 × 10-4), especially in conotruncal defect with OR of 2.37 (p = 1.77 × 10-3) and atrioventricular septal defect with OR of 3.14 (p = 0.0194). Interestingly, there is a significant relationship between those variants that have an allele frequency below 0.01% and atrioventricular septal defect, which is the phenotype observed previously in a homozygous N-ethyl-N-nitrosourea (ENU)-induced Lrp1 mutant mouse line.

  View details for DOI 10.3390/genes14040947

  View details for Web of Science ID 000977574000001

  View details for PubMedID 37107705

  View details for PubMedCentralID PMC10137934