Biology subjects

Heinrich, A.

Publications and source records attributed to Heinrich, A..

4 recordsLinked to original sources

bioRxiv2025

The VelB intrinsically disordered domain promotes selective heterodimer formation of velvet domain regulatory proteins for fungal development

Fungi possess several transcription factors with a characteristic velvet domain for DNA-binding and homo- or heterodimerization, which is structurally similar to the mammalian NF-B Rel homology domain. Velvet dimers control fungal development, virulence and mycotoxin formation. VelB is the only regulator, which carries an intrinsically disordered domain (IDD) within the velvet domain. The IDD as well as the positioning within VelB is conserved in the fungal kingdom. Intrinsically disordered regions contribute to transcription activation and DNA binding and frequently appear in eukaryotic transcription factors. The VelB IDD provides selective heterodimerization as well as protein stability control. The IDD is not required for the formation of the VelB-VeA heterodimer of Aspergillus nidulans or Verticillium dahliae, but promotes the formation of the VelB-VosA heterodimer. The IDD destabilizes VelB single molecules and also balances its distribution and ratio between both velvet heterodimers. These balances contribute to control appropriate mycotoxin production and sexual development. Herewith, the VelB IDD represents a novel control mechanism of velvet protein stability and heterodimer formation for precise priming of fungal development.

molecular biology↗

bioRxiv2022

Testicular macrophages are recruited during a narrow time window by fetal Sertoli cells to promote organ-specific developmental functions

While macrophages are most commonly known for their roles in innate immunity, a growing body of evidence supports the idea that fetal-derived tissue-resident macrophages play developmental roles during organogenesis. In the testis, it has long been proposed that macrophages are important players in steroidogenesis and other testicular functions, but which macrophage populations are involved is unclear. We previously showed that macrophages play critical roles in fetal testis morphogenesis and reported the presence of 2 unique adult testicular macrophage populations, interstitial and peritubular. There has been some debate regarding the hematopoietic origins of testicular macrophages and whether distinct macrophage populations promote specific testicular functions. Here we have undertaken an extensive lineage-tracing study of mouse hematopoietic cells. We found that, while yolk-sac-derived macrophages comprise the earliest testicular macrophages, fetal hematopoietic stem cells (HSCs) give rise to monocytes that colonize the gonad during a narrow time window in mid-gestation, after which time HSCs no longer contribute to testicular macrophages. These long-lived monocytes, over the course of fetal and postnatal life, differentiate into testicular macrophages. Our data indicate that Sertoli cells, and not germ cells, are required for recruitment of immune cells and peritubular macrophage differentiation. Finally, we show that yolk-sac-derived macrophages and HSC-derived macrophages play distinct roles in testis cord morphogenesis, whereas interstitial macrophages promote adult Leydig cell proliferation and steroid production. Overall, our findings offer clarity regarding the origins of testicular macrophages and provide insight into the diversity of their tissue-specific developmental roles.

developmental biology↗

bioRxiv2021

Cdc42 activity in Sertoli cells is essential for maintenance of spermatogenesis

Sertoli cells are highly polarized testicular supporting cells that simultaneously nurture progressively maturing germ cells. Proper localization of polarity protein complexes within Sertoli cells, including those responsible for blood-testis barrier formation, are vital for successful spermatogenesis. However, the mechanisms and developmental timing that underlie the establishment of polarity are poorly understood. To investigate this aspect of testicular function, we conditionally deleted Cdc42, encoding a Rho GTPase involved in regulating cell polarity, specifically in Sertoli cells. Cdc42 deletion disrupted adult Sertoli cell maturation and localization of polarity proteins, but did not affect fetal and early postnatal testicular development, nor the onset of the first wave of spermatogenesis. By early adulthood, however, conditional knockout males exhibited a loss of spermatogenic cells, resulting in a complete lack of sperm. These findings demonstrate that Cdc42 plays an essential role in establishing adult Sertoli cell polarity and, thus, maintaining steady-state spermatogenesis and healthy sperm production.

developmental biology↗

bioRxiv2021

Loss of Mafb and Maf distorts myeloid cell ratios and disrupts fetal mouse testis vascularization and organogenesis

Testis differentiation is initiated when Sry in pre-Sertoli cells directs the gonad toward a male-specific fate. Sertoli cells are essential for testis development, but cell types within the interstitial compartment, such as immune and endothelial cells, are also critical for organ formation. Our previous work implicated macrophages in fetal testis morphogenesis, but little is known about genes underlying immune cell development during organogenesis. Here we examine the role of the immune-associated genes Mafb and Maf in mouse fetal gonad development, and we demonstrate that deletion of these genes leads to aberrant hematopoiesis manifested by supernumerary gonadal monocytes. Mafb;Maf double knockout embryos underwent initial gonadal sex determination normally, but exhibited testicular hypervascularization, testis cord formation defects, Leydig cell deficit, and a reduced number of germ cells. In general, Mafb and Maf alone were dispensable for gonad development; however, when both genes were deleted, we observed significant defects in testicular morphogenesis, indicating that Mafb and Maf work redundantly during testis differentiation. These results demonstrate previously unappreciated roles for Mafb and Maf in immune and vascular development and highlight the importance of interstitial cells in gonadal differentiation. Summary statementDeletion of Mafb and Maf genes leads to supernumerary monocytes in fetal mouse gonads, resulting in vascular, morphogenetic, and differentiation defects during testicular organogenesis.

developmental biology↗