Biology subjects

Sucov, H. M.

Publications and source records attributed to Sucov, H. M..

3 recordsLinked to original sources

bioRxiv2024

Lineage-specific intersection of endothelin and GDNF signaling in enteric nervous system development

Two major ligand-receptor signaling axes - endothelin Edn3 and its receptor Ednrb, and glial-derived neurotrophic factor (GDNF) and its receptor Ret - are required for migration of enteric nervous system (ENS) progenitors to the hindgut. Mutations in either component cause colonic aganglionosis, also called Hirschsprung disease. Here, we have used Wnt1Cre and Pax2Cre in mice to show that these driver lines label distinct ENS lineages during progenitor migration and in their terminal hindgut fates. Both Cre lines result in Hirschsprung disease when combined with conditional Ednrb or conditional Ret alleles. In vitro explant assays and analysis of lineage-labeled mutant embryos show that GDNF but not Edn3 is a migration cue for cells of both lineages. Instead, Edn3-Ednrb function is required in both for GDNF responsiveness albeit in different ways: by expanding the Ret+ population in the Pax2Cre lineage, and by supporting Ret function in Wnt1Cre-derived cells. Our results demonstrate that two distinct lineages of progenitors give rise to the ENS, and that these divergently utilize endothelin signaling to support migration to the hindgut.

developmental biology↗

bioRxiv2022

Purkinje cardiomyocytes of the ventricular conduction system are highly diploid but not regenerative

Inefficiency of regeneration underlies many of the pathologies associated with heart injury and disease. Ventricular diploid cardiomyocytes (CMs) are a candidate population that may have enhanced proliferative and regenerative properties [1-3], but subpopulations of diploid CMs and their regenerative capacities are not yet known. Here, using the expression marker Cntn2-GFP and the lineage marker Etv1CreERT2, we demonstrate that peripheral ventricular conduction CMs (Purkinje CMs) are disproportionately diploid (35%, vs. 4% of bulk ventricular CMs). However, this lineage had no enhanced competence to support regeneration after adult infarction. Furthermore, the CM-specific kinase Tnni3k, which strongly influences bulk ventricular CM ploidy [3] and is also associated with conduction system defects [4], had no influence on the ploidy or organization of the ventricular conduction system. Unlike the bulk diploid CM population, a significant fraction of conduction CMs remain diploid by avoiding neonatal cell cycle activity, likely contributing to these properties.

developmental biology↗

bioRxiv2022

CITED2 Is A Conserved Regulator Of Deep Hemochorial Placentation

Establishment of the hemochorial uterine-placental interface requires exodus of trophoblast cells from the placenta and their transformative actions on the uterus, which represent processes critical for a successful pregnancy, but are poorly understood. We examined the involvement of CBP/p300-interacting transactivator with glutamic acid/aspartic acid-rich carboxyl terminal domain 2 (CITED2) in rat and human trophoblast cell development. The rat and human exhibit deep hemochorial placentation. CITED2 was distinctively expressed in the junctional zone and invasive trophoblast cells of the rat. Homozygous Cited2 gene deletion resulted in placental and fetal growth restriction. Small Cited2 null placentas were characterized by disruptions in the junctional zone, delays in intrauterine trophoblast cell invasion, and compromised plasticity. In the human placentation site, CITED2 was uniquely expressed in the extravillous trophoblast (EVT) cell column and importantly contributed to development of the EVT cell lineage. We conclude that CITED2 is a conserved regulator of deep hemochorial placentation. Significance StatementThe process of establishing the uterine-placental interface is a poorly understood tissue re-engineering event that involves genetically foreign trophoblast cells breaching the immunologically secure uterus. When optimal, mother and fetus thrive, whereas failures represent the root cause of life-threatening diseases of pregnancy. CBP/p300-interacting transactivator with glutamic acid/aspartic acid-rich carboxyl terminal domain 2 (CITED2) is a transcriptional co-regulator with a conspicuous presence in trophoblast cell lineages infiltrating the uterine parenchyma. CITED2 helps coordinate the differentiation of rat and human trophoblast cells into invasive/extravillous trophoblast cells capable of transforming the uterus. These actions ensure requisite placental development and adaptations to physiological stressors. CITED2 exemplifies a conserved regulator of transcriptional events essential for establishing the uterine-placental interface.

developmental biology↗