Isolation of a Murine Homologue of the Drosophila neuralized Gene, a Gene Required for Axonemal Integrity in Spermatozoa and Terminal Maturation of the Mammary Gland

Abstract

The Drosophila neuralized gene shows genetic interactions with Notch, Enhancer of split, and other neurogenic genes and is thought to be involved in cell fate specification in the central nervous system and the mesoderm. In addition, a human homologue of the Drosophila neuralized gene has been described as a potential tumor suppressor gene in malignant astrocytomas. We have isolated a murine homologue of the Drosophila and human Neuralized genes and, in an effort to understand its physiological function, derived mice with a targeted deletion of this gene. Surprisingly, mice homozygous for the introduced mutation do not show aberrant cell fate specifications in the central nervous system or in the developing mesoderm. This is in contrast to mice with targeted deletions in other vertebrate homologues of neurogenic genes such as Notch, Delta, and Cbf-1. Male Neuralized null mice, however, are sterile due to a defect in axoneme organization in the spermatozoa that leads to highly compromised tail movement and sperm immotility. In addition, female Neuralized null animals are defective in the final stages of mammary gland maturation during pregnancy.

Neuralized-2 Regulates a Notch Ligand in Cooperation with Mind Bomb-1

“…Targeted disruption of notch1 expression or disruption of its downstream targets in mice leads to embryonic lethality by developmental defects (43)(44)(45)(46). However, mice with disrupted neur1 exhibit no abnormal cell fate specifications during neurogenesis and somitogenesis, two processes in which Notch signaling has been shown to be involved (25,26). This discrepancy might be due to functional redundancy provided by Neur2.…”

“…1, A and B). Mouse Neur1 and Neur2 both have two Neuralized homology repeat (NHR) domains and a RING finger domain (25,26,30). Furthermore, comparison between mouse Neur1 and Neur2 subdomains showed a higher degree of homology, with 49, 42, and 70% identities in the NHR1, NHR2, and RING finger domains, respectively (data not shown).…”

“…neur2 was expressed at high levels in the brain and kidney and at low levels in the heart (Fig. 1F), whereas neur1 was expressed at high levels in the brain and skeletal muscle (25,26). The different expression patterns of these two genes suggest distinct roles of Neur1 and Neur2 in adults.…”

“…Recent studies have suggested that DNeur is a ubiquitin-protein isopeptide ligase (E3) that promotes the internalization and degradation of Delta to activate the Notch signaling pathway (10,11,24). However, mice with a disrupted neur1 (neur1 was heretofore known as neuralized in mice) gene are viable; they do not show any Notch-related phenotype during embryogenesis but do exhibit defects as adults, including impaired olfactory discrimination, hypersensitivity to ethanol, and abnormalities both in axoneme organization in the spermatozoa and in mammary gland maturation during pregnancy (25,26). Thus, we speculate that other vertebrate neur homolog(s) might compensate for loss of the neur gene in mammals based on the conservation between Drosophila and mammalian Notch signaling.…”

Endocytosis in Notch Signaling Activation

“…Quite surprisingly, inactivation of these genes does not result in major phenotypic defects [240][241][242]. Only subtle defects were scored in Neurl1 -/-mice: (i) male mutants are sterile due to a defect in the axonemal organization of spermatozoa that leads to immotile sperm [242]; (ii) female KOs are defective in the final stages of mammary gland maturation during pregnancy [242]; (iii) Neurl1 -/-mice are hypersensitive to ethanol effects on motor coordination and exhibit a defect in olfactory discrimination [241]. Only these latter defects can be putatively connected to an impairment of some subtle (yet to be defined) function of Notch in mammalian neurons, but no classical Notch signaling defects are identifiable in these mutants.…”