Cell-cell signaling during hypothalamic neuron development
The hypothalamus is a critical center for homeostasis in the body and is essential for feeding, growth and reproduction, among other things. The neuroendocrine hypothalamus arises from progenitors lining the third ventricle of the brain. Obesity, infertility and dwarfism can be linked to aberrant development of these neurons. Despite the importance of this brain region to normal physiology, little is known about the factors that are necessary to get the wide variety of peptide producing neurons.
We have a focus on the Notch signaling pathway, which we hypothesize plays an important role in the proliferation and lineage specific differentiation of hypothalamic progenitor cells. We are exploring if Notch signaling is necessary and sufficient for obtaining the full complement of cells in the Arcuate Nucleus of the hypothalamus by employing transgenic and knockout mice. These studies also take advantage of molecular genetic techniques and whole animal physiology. We have an exciting collaboration with the Underhill lab that involves isolating hypothalamic stem cells and culturing them on engineered arrays so that we can test a wide variety of tethered and secreted stimuli that may influence neuron development. We are also interested in how maternal environment, including obesity or exposure to endocrine disrupting chemicals can impact hypothalamic progenitors.
The overall goal of these studies is to define the normal complement of signals that stem cells use to make fate choices in the hypothalamus. This information will be useful in finding causes for congenital neuroendocrine disorders. It also may be possible to someday engineer new neurons to replace those that don’t develop correctly or those that are damaged by brain injury.
We have collaborations with Jonathan Sweedler (Peptidomics), Jodi Flaws (Toxicology) and Greg Underhill (Bioengineering).
Moran T.B., Goldberg L.B., Serviss, S., and Raetzman L.T. (2011). Numb deletion in POMC expressing cells impairs pituitary intermediate lobe cell adhesion, progenitor cell localization, and neuro-intermediate lobe boundary formation. Mol. Endocrinol., 25, 117-27. *Featured in Endocrine News.
Himes A.D., Fiddler R., and Raetzman L.T. (2011). N-cadherin loss in POMC expressing cells leads to pituitary disorganization. Mol. Endocrinol., 25, 482-91. *Featured on the cover.
Aujla P.K., Bora A., Monahan P., Sweedler J.V., and Raetzman L.T. (2011). The Notch effector gene Hes1 regulates migration of hypothalamic neurons, neuropeptide content and axon targeting to the pituitary. Dev. Biol. 353, 61-71.
Goldberg L.B., Aujla P.K., and Raetzman L.T. (2011). Persistent expression of activated Notch inhibits corticotrope and melanotrope differentiation and results in dysfunction of the HPA axis. Dev. Biol. 358, 23-32.
Monahan P., Himes A.D., Parfieniuk A., and Raetzman L.T. (2012). P21, an important mediator of quiescence during pituitary tumor formation, is dispensable for normal pituitary development. Mech. Dev., 128, 640-52.
Moran T.B., Brannick K.E., and Raetzman L.T. (2012). Aryl hydrocarbon receptor activity modulates prolactin expression in the pituitary. Toxicol. Appl. Pharmacol., 265, 139-45.
Brannick K.E., Craig Z.R., Himes A.D., Peretz J.R., Wang W., Flaws J.A., and Raetzman L.T. (2012). Prenatal exposure to low doses of bisphenol A increases pituitary proliferation and gonadotroph number in female offspring at birth. Biol. Reprod. 87, 82, 1-10.
Aujla P.K., Naratadam G.T., Xu L., and Raetzman L.T. (2013). Notch/Rbpjk signaling regulates progenitor maintenance and differentiation of hypothalamic arcuate neurons. Development, 140, 3511-21.
Nantie L.B., Himes A.D., Getz D.R., and Raetzman L.T. (2014). Notch signaling in postnatal pituitary expansion: proliferation, progenitors and cell specification. Mol. Endocrinol., 28, 731-44.
Aujla P.K., Bogdanovic V., Naratadam G.T., and Raetzman L.T. (2015). Persistent expression of activated Notch in the developing hypothalamus affects survival of pituitary progenitors and alters pituitary structure. Dev. Dyn., 244: 921-34. *Featured on the cover
Biehl M.J. and Raetzman L.T. (2015). Rbpj-? mediated Notch signaling plays a critical role in development of hypothalamic Kisspeptin neurons Dev. Biol., 406:235-46.