Mammals and birds have a specialized cardiac atrioventricular conduction system enabling rapid activation of both ventricles. This system may have evolved together with high heart rates to support their endothermic state (warm-bloodedness) and is seemingly lacking in ectothermic vertebrates from which first mammals then birds independently evolved. Here, we studied the conduction system in crocodiles (Alligator mississippiensis), the only ectothermic vertebrates with a full ventricular septum. We identified homologues of mammalian conduction system markers (Tbx3-Tbx5, Scn5a, Gja5, Nppa-Nppb) and show the presence of a functional atrioventricular bundle. The ventricular Purkinje network, however, was absent and slow ventricular conduction relied on trabecular myocardium, as it does in other ectothermic vertebrates. We propose the evolution of the atrioventricular bundle followed full ventricular septum formation prior to the development of high heart rates and endothermy. In contrast, the evolution of the ventricular Purkinje network is strongly associated with high heart rates and endothermy.

• Keywords
• American alligator, Tbx3, Ventricular septum, conduction system, developmental biology, evolution, evolutionary biology, genomics, stem cells,
• MeSH
• Alligators and Crocodiles embryology   genetics   physiology   MeSH
• Embryo, Nonmammalian metabolism   MeSH
• Bundle of His embryology   metabolism   physiology   MeSH
• In Situ Hybridization MeSH
• Ventricular Septum embryology   metabolism   physiology   MeSH
• Models, Cardiovascular MeSH
• Heart Conduction System embryology   physiology   MeSH
• T-Box Domain Proteins genetics   metabolism   MeSH
• Purkinje Fibers embryology   metabolism   physiology   MeSH
• Heart embryology   physiology   MeSH
• Heart Rate genetics   physiology   MeSH
• Heart Ventricles embryology   metabolism   MeSH
• Gene Expression Regulation, Developmental MeSH
• Animals MeSH
• Check Tag
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• T-Box Domain Proteins MeSH

Among lizards, only monitor lizards (Varanidae) have a functionally divided cardiac ventricle. The division results from the combined function of three partial septa, which may be homologous to the ventricular septum of mammals and archosaurs. We show in developing monitors that two septa, the 'muscular ridge' and 'bulbuslamelle', express the evolutionarily conserved transcription factors Tbx5, Irx1 and Irx2, orthologues of which mark the mammalian ventricular septum. Compaction of embryonic trabeculae contributes to the formation of these septa. The septa are positioned, however, to the right of the atrioventricular junction and they do not participate in the separation of incoming atrial blood streams. That separation is accomplished by the 'vertical septum', which expresses Tbx3 and Tbx5 and orchestrates the formation of the electrical conduction axis embedded in the ventricular septum. These expression patterns are more pronounced in monitors than in other lizards, and are associated with a deep electrical activation near the vertical septum, in contrast to the primitive base-to-apex activation of other lizards. We conclude that evolutionarily conserved transcriptional programmes may underlie the formation of the ventricular septa of monitors.

• Keywords
• Evolution, Heart, Lizard, Ventricular septum,
• MeSH
• Time-Lapse Imaging MeSH
• Echocardiography veterinary   MeSH
• Embryo, Nonmammalian MeSH
• Homeodomain Proteins genetics   physiology   MeSH
• Lizards embryology   genetics   MeSH
• Ventricular Septum diagnostic imaging   embryology   MeSH
• Evolution, Molecular MeSH
• T-Box Domain Proteins genetics   physiology   MeSH
• Heart Ventricles diagnostic imaging   embryology   MeSH
• Heart Atria diagnostic imaging   embryology   MeSH
• Myosin Heavy Chains genetics   metabolism   MeSH
• Gene Expression Regulation, Developmental MeSH
• Animals MeSH
• Check Tag
• Animals MeSH
• Publication type
• Video-Audio Media MeSH
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Homeodomain Proteins MeSH
• T-Box Domain Proteins MeSH
• T-box transcription factor 5 MeSH Browser
• Myosin Heavy Chains MeSH

Because the causes of combined pituitary hormone deficiency (CPHD) are complex, the etiology of congenital CPHD remains unknown in most cases. The aim of the study was to identify the genetic etiology of CPHD in a well-defined single-center cohort. In total, 34 children (12 girls) with congenital CPHD (growth hormone (GH) deficiency and impaired secretion of at least one other pituitary hormone) treated with GH in our center were enrolled in the study. Their median age was 11.2 years, pre-treatment height was -3.2 s.d., and maximal stimulated GH was 1.4 ug/L. Of them, 30 had central adrenal insufficiency, 27 had central hypothyroidism, ten had hypogonadotropic hypogonadism, and three had central diabetes insipidus. Twenty-six children had a midline defect on MRI. Children with clinical suspicion of a specific genetic disorder underwent genetic examination of the gene(s) of interest via Sanger sequencing or array comparative genomic hybridization. Children without a detected causal variant after the first-tier testing or with no suspicion of a specific genetic disorder were subsequently examined using next-generation sequencing growth panel. Variants were evaluated by the American College of Medical Genetics standards. Genetic etiology was confirmed in 7/34 (21%) children. Chromosomal aberrations were found in one child (14q microdeletion involving the OTX2 gene). The remaining 6 children had causative genetic variants in the GLI2, PROP1, POU1F1, TBX3, PMM2, and GNAO1 genes, respectively. We elucidated the cause of CPHD in a fifth of the patients. Moreover, our study supports the PMM2 gene as a candidate gene for CPHD and suggests pathogenic variants in the GNAO1 gene as a potential novel genetic cause of CPHD.

• Keywords
• combined pituitary hormone deficiency, genetics of short stature, growth hormone deficiency, next-generation sequencing, short stature,
• Publication type
• Journal Article MeSH