Date of Award

Fall 2007

Project Type

Dissertation

Program or Major

Biochemistry

Degree Name

Doctor of Philosophy

First Advisor

Stacia A Sower

Abstract

The vertebrate hypothalamic-pituitary-gonadal (HPG) and hypothalamic-pituitary-thyroid (HPT) endocrine axes involve specific interaction between pituitary glycoprotein hormones GpH (lutropin LH, follitropin FSH, thyrotropin TSH) and glycoprotein hormone receptors GpH-R (LH-R, FSH-R and TSH-R respectively).

GpHs and GpH-Rs originate in a common ancestral ligand/receptor pair. Their duplications were followed by divergent evolution resulting in the emergence of a novel, pituitary/peripheral gland control level. It is estimated that this occurred more than 500 million years ago (mya), before or concomitant with the divergence of the jawed vertebrates (Gnathostomes) lineage from their jawless (Agnathan) ancestors. This coincides with the estimated time of divergence of the lamprey lineage, one of the two surviving Agnathan groups (lamprey and hagfishes) in the actual fauna. Therefore, the study of the GpH/GpH-R system in lamprey is of foremost importance for understanding the evolutionary emergence of the HPG and HPT axes. Recently, a pituitary glycoprotein similar with the GpH beta chain was identified in this species.

Two glycoprotein hormone receptors (IGpH-R I and IGpH-R II of 719 and 781 residues respectively) highly similar with Gnathostome GpH-Rs were cloned from sea lamprey testes and thyroid respectively. The highest tissue transcript levels were found by RT-PCR in testes and thyroid respectively and their exon/intron organization is almost identical with that of mammalian FSH-R and TSH-R. Mammalian LH induces a low but detectable increase in CAMP concentration in the cells transfected with IGpH-R I. Functional assays on lamprey GpH-R I/rat LH-R domain swapped chimeric receptors suggest that IGpH-R I domains conserved their function. Alteration of the 'hinge' or Signaling Specificity Domain (SSD) segment of IGpH-R I by insertion/replacement with rat corresponding fragments results in a drastic change in sensitivity to ol-H which is also dependent on domain composition of the chimera.

Therefore we hypothesize that one GpH in lamprey interacts with two GpH-Rs in gonads and thyroid as part of a primitive HPG/T axis which antecedes the divergence of the Gnathostome HPG and HPT systems.

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