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  4. Aimee Ryan

Brn-1, Brn-2 biology

Aimee Ryan

Appointment Period: 1994-1995 / Grant Year: [10]

Aimee RyanThe two interrelated projects that I have participated in during the period of this support are: (1) The role of POU-domain transcription factors in CNS and PNS development; and (2) Early pituitary development.

A fundamental aspect of the development of complex organ systems is a requirement for precise temporal and spatial coordination in the genesis of tissues of distinct embryonic origins, in order to form functional units required for physiological homeostasis and survival. Such a requirement is particularly well exemplified in mammalian development in the formation of the hypothalamic-pituitary axis. Neuronally expressed POU domain factors might exert effects on terminal differentiation events similar to those of Pit-1 in the maturation of anterior pituitary gland cell phenotypes. Neurons comprising the endocrine hypothalamus develop in tandem with their ultimate target, the pituitary gland, and arise from a primordium in which three related class III POU domain factors-Brn-2, Brn-4, and Brn-1-are initially co-expressed. These factors subsequently exhibit stratified patterns of ontogenic expression, correlating with the appearance of distinct neuropeptides that define three major endocrine hypothalamic cell types. Thus, both neuronal and endocrine components of the hypothalamic-pituitary axis are critically dependent upon the action of specific POU domain factors at a penultimate step in the sequential events that underlie the appearance of mature cellular phenotypes.

More recently, we have examined the role of the neurally expressed genes Brn-3.1 and Brn-3.2, which are mammalian orthologues of the Caenorhabditis elegans unc-86 gene that constitute, with Brn-3.0, the class IV POU-domain transcription factors. Brn-3.1 and Brn-3.2 provide a means of exploring the potentially distinct biological functions of expanded gene families in neural development. The highly related members of the Brn-3 family have similar DNA-binding preferences and overlapping expression patterns in the sensory nervous system, midbrain and hindbrain, suggesting functional redundancy. We were able to demonstrate that Brn-3.1 and Brn-3.2 critically modulate the terminal differentiation of distinct sensorineural cells in which they exhibit selective spatial and temporal expression patterns.

During this award I received considerable training in the use of immunohistochemical and in situ hybridization methodology, including tissue fixation, cryosectioning, immunohistochemical staining, whole mount immunohistochemistry and in situ hybridization. In addition, I have gained considerable theoretical knowledge with respect to neural anatomy and CNS and pituitary development. This training support ideally complemented my background in molecular biology and biochemistry.

PUBLICATIONS (resulting from this training)

Schonemann MD, Ryan AK, McEvilly RJ, O'Connell SM, Arias CA, Kalla KA, Li P, Sawchenko PE, Rosenfeld MG. (1995) Development and survival of the endocrine hypothalamus and posterior pituitary gland requires the neuronal POU domain factor Brn-2. Genes Dev. 9:3122-35.

Rosenfeld MG, Bach I, Erkman L, Li P, Lin C, Lin S, McEvilly R, Ryan A, Rhodes S, Schonnemann M, Scully K. (1996) Transcriptional control of cell phenotypes in the neuroendocrine system. Recent Prog Horm Res. 51:217-38.

Erkman L, McEvilly RJ, Luo L, Ryan AK, Hooshmand F, O'Connell SM, Keithley EM, Rapaport DH, Ryan AF, Rosenfeld MG. (1996) Role of transcription factors Brn-3.1 and Brn-3.2 in auditory and visual system development. Nature. 381:603-6.

Szeto DP, Ryan AK, O'Connell SM, Rosenfeld MG. (1996) P-OTX: a PIT-1-interacting homeodomain factor expressed during anterior pituitary gland development. Proc Natl Acad Sci USA 93:7706-10.

McEvilly RJ, Erkman L, Luo L, Sawchenko PE, Ryan AF, Rosenfeld MG. (1996) Requirement for Brn-3.0 in differentiation and survival of sensory and motor neurons. Nature. 384:574-7.

Sornson MW, Wu W, Dasen JS, Flynn SE, Norman DJ, O'Connell SM, Gukovsky I, Carriere C, Ryan AK, Miller AP, Zuo L, Gleiberman AS, Andersen B, Beamer WG, Rosenfeld MG. (1996) Pituitary lineage determination by the Prophet of Pit-1 homeodomain factor defective in Ames dwarfism. Nature. 384:327-33.

Ryan AK, Rosenfeld MG. (1997) POU domain family values: flexibility, partnerships, and developmental codes. Genes Dev. 11:1207-25.

Labosky PA, Winnier GE, Jetton TL, Hargett L, Ryan AK, Rosenfeld MG, Parlow AF, Hogan BL. (1997) The winged helix gene, Mf3, is required for normal development of the diencephalon and midbrain, postnatal growth and the milk-ejection reflex. Development. 124:1263-74.

Ryan AK, Blumberg B, Rodriguez-Esteban C, Yonei-Tamura S, Tamura K, Tsukui T, de la Pena J, Sabbagh W, Greenwald J, Choe S, Norris DP, Robertson EJ, Evans RM, Rosenfeld MG, Izpisua Belmonte JC. (1998) Pitx2 determines left-right asymmetry of internal organs in vertebrates. Nature. 394:545-51.

Schonemann MD, Ryan AK, Erkman L, McEvilly RJ, Bermingham J, Rosenfeld MG. (1998) POU domain factors in neural development. Adv Exp Med Biol. 449:39-53.

Shimazaki T, Arsenijevic Y, Ryan AK, Rosenfeld MG, Weiss S. (1999) A role for the POU-III transcription factor Brn-4 in the regulation of striatal neuron precursor differentiation. EMBO J. 18:444-56.

Szeto DP, Rodriguez-Esteban C, Ryan AK, O'Connell SM, Liu F, Kioussi C, Gleiberman AS, Izpisua-Belmonte JC, Rosenfeld MG. (1999) Role of the Bicoid-related homeodomain factor Pitx1 in specifying hindlimb morphogenesis and pituitary development. Genes Dev. 13:484-94.

Friedman RA, Adir Y, Crenshaw EB, Ryan AF, Rosenfeld MG. (2000) A transgenic insertional inner ear mutation on mouse chromosome 1. Laryngoscope. 110:489-96.

Rosenfeld MG, Briata P, Dasen J, Gleiberman AS, Kioussi C, Lin C, O'Connell SM, Ryan A, Szeto DP, Treier M. (2000) Multistep signaling and transcriptional requirements for pituitary organogenesis in vivo. Recent Prog Horm Res. 55:1-13.