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Thyroid hormone (TH) insufficiency causes variable hearing impairment and mental deficiency in humans. Rodents lacking TH have congenital hearing deficiency that has been attributed to physiologic, morphologic, and developmental abnormalities of the auditory system. We examined four genetically defined strains of hypothyroid mice for development of hearing and response to TH replacement initiated during late gestation and continued through six weeks of age. Auditory brain stem response studies showed variable hearing impairment in homozygous mutants of each strain at three weeks of age relative to normal littermates. Mutants from three of the strains still had hearing deficiencies at six weeks of age. TH-enriched diet significantly improved hearing in three-week-old mutants of each strain relative to untreated mutants. Differences in the level of hearing impairment between the Prop1df and Pit1dw mutants, which have defects in the same developmental pathway, were determined to be due to genetic background modifier genes. Further physiologic and morphologic studies in the Cgatm1Sac strain indicated that poor hearing was due to cochlear defects. We conclude that TH supplement administered during the critical period of hearing development in mice can prevent deafness associated with congenital hypothyroidism of heterogeneous genetic etiology.

Prop1 is one of several transcription factors important for the development of the pituitary gland. Downstream targets of PROP1 and other critical pituitary transcription factors remain largely unknown. We have generated a partial expression profile of the developing pituitary gland containing over 350 transcripts, using cDNA subtractive hybridization between Prop1 df/df and wild-type embryonic pituitary gland primordia. Numerous classes of genes including transcription factors, membrane associated mol- ecules, and cell cycle regulators were identified in this study. Of the transcripts, 34% do not have sequence similarity to known genes, but are similar to ESTs, and 4% represent novel sequences. Pituitary gland expression of a number of clones was verified using in situ hybridization. Several members of the Wnt signaling pathway were identified in the developing pituitary gland. The frizzled2 receptor, Apc, b-catenin, groucho, and a novel isoform of TCF4 (officially named Tcf7l2) were identified in developing pituitary libraries. Three N- terminal alternatively spliced Tcf7l2 isoforms are reported here, each of which lacks a DNA-binding domain. Functional studies indicate that these isoforms can act as endogenous inhibitors of Wnt signaling in some contexts. This is the first report of Tcf7l2 and Fzd2 expression in the developing pituitary. These molecules may be important in medi- ating Wnt signaling during pituitary ontogeny. We expect other transcripts from these libraries to be involved in pituitary gland development.

The pituitary gland functions as an intermediary between the brain and the peripheral endocrine organs of the body (Tortora and Grabowski 1996). In the context of a complex system of feedback control, the pituitary gland relays signals from the hypothalamus to its target organs by secreting various hormones. These hormone signals, which are transmitted throughout the endocrine system, reflect the current homeostatic conditions of the body. Mechanisms of compensation, including the regulation of gene transcription, hormone secretion, and cell proliferation, allow the pituitary to respond to the continually changing needs of the organism. It is in this way that the pituitary aids in the regulation of many vital processes, including growth, metabolism, reproduction, and stress response. The mammalian pituitary is comprised of three lobes: the posterior lobe, the intermediate lobe, and the anterior lobe. The anterior lobe of the pituitary is composed of functionally distinct cell types that are the primary site of endocrine regulation. During embryogenesis, the anterior and intermediate lobes of the pituitary develop from an invagination in the oral ectoderm known as Rathke’s pouch (Dubois and ElAmraoui 1995). The pouch eventually separates from the oral ectoderm and undergoes a period of intense proliferation. This is followed by differentiation into the five anterior pituitary cell types on the rostral side of the pouch and the intermediate lobe melanotropes on the caudal side of the pouch (Dubois and Hemming 1991). By birth, the anterior pituitary is composed of functioning corticotropes, thyrotropes, somatotropes, gonadotropes, and lactotropes that produce adrenocorticotropic hormone (ACTH), thyroid-stimulating hormone (TSH), growth hormone (GH), gonadotropins (FSH and LH), and prolactin (PRL), respectively. Expression of each hormone gene, which defines the terminal differentiation of each cell type, occurs in a spatially and temporally specific manner during pituitary organogenesis (Japon et al. 1994; Burrows et al. 1999). The mechanisms that control this process involve the secretion of signals from surrounding structures and the expression of a cascade of homeodomain transcription factors. Studies in both mouse and human reveal that control of signaling events and homeobox gene expression is essential for proper pituitary gland development (Watkins-Chow and Camper 1998; Dasen and Rosenfeld 1999). Deregulation of these events can lead to various forms of pituitary gland dysfunction, including hypopituitarism and adenomas.

Species: Mouse Locus name: Zinc finger protein 15 Locus symbol: Zfp15 Map position: Zfp15 is localized on mouse Chromosome (Chr) 4: centromere-D4Bir11-7.4 + 2.7-Zfp15-1.1 + 1.1-D4Mit4-17.0 + 3.9-D4Bir16-7.4 +_ 2.7-(D4Mit9, D4Bir20)--4.3 + 2.1-D4Bir2110.6 + 3.2-D4Mit11-5.4 + 2.4-D4Bir23-3.2 + 1.8-D4Bir24-8.5 + 2.9-(D4Mit13, Pnd, D4Bir25, D4Mit14)-l.1 + 1.1-D4Mit42-6.4 + 2.5-(Dvl, Rnr4)-telomere. Method of mapping: Zfp15 was localized by haplotype analysis of 94 progeny from an interspecific backcross, (C57BL/6J x M. spretus)F 1 x C57BL/6J [1]. Molecular reagents used for mapping: The Zfp15 probe was obtained by polymerase chain reaction amplification of a 552-bp fragment from mouse pituitary cDNA with primers designed on the basis of the rat Zfpl5 cDNA sequence [2]. The primers amplify 465 bp of coding sequence, outside of the conserved zinc finger regions, corresponding to the last 154 amino acids, and 87 bp of the 3' untranslated region. The RT-PCR product was cloned into the pGEM4Z vector and sequenced to confirm its correspondence with the rat Zfpl5 cDNA. Allele detection: A BglI polymorphism was detected in mouse genomic DNA with the Zfp15 probe, resulting in an M. spretusspecific restriction fragment of 15 kb and a common restriction fragment of 24 kb. The mapping was confirmed with a BamHI polymorphism, resulting in two M. spretus-specific restriction fragments of 8.9 and 6.6 kb and two common fragments of 18 and 5.5 kb.