SP4, A MEMBER OF THE SP1-FAMILY OF ZINC-FINGER TRANSCRIPTION FACTORS,IS REQUIRED FOR NORMAL MURINE GROWTH, VIABILITY, AND MALE-FERTILITY

We report the cloning, characterization, and targeting of an Sp1-relat ed zinc finger transcription factor gene from the distal arm of mouse chromosome 12. This gene, previously identified in rats and humans and designated sp4, is homologous to the Drosophila buttonhead (btd) gene , which is expressed in the head region of developing flies. Similarly , in situ hybridizations show that sp4 is highly expressed in mouse em bryos in the developing central nervous system (CNS). Expression of sp 4 is seen as early as Day 9 of development, where transcripts are abun dant in the posterior neuropore. Expression in later embryos is detect ed throughout the CNS as well as in other structures, including the na sal mucosa, the vomeronasal organ, the epithelium of the lung and inte stinal tract, the testes, and the developing teeth. Northern blot anal ysis showed sp4 expression in the adult brain and other tissues. Gene targeting by homologous recombination was used to determine the role o f sp4 during mouse development. Two-thirds of homozygous mutants die w ithin the first few days after birth and those that survive are smalle r than their wild-type littermates. While fertility of the female muta nts appears normal, homozygous mutant males do not breed, despite havi ng histologically intact testes containing mature sperm. sp4/sp4 mutan t males fail to copulate, indicating that this gene is required for no rmal male reproductive behavior. (C) 1996 Academic Press, Inc.