The Effect Of Ras Signaling Pathway On The Development Of Female Reproductive Tract

BackgroundThe abnormalities in organs developed from mullerian duct draw suspicions if defects in mullerian duct development play a role in Mayer-Rokitansky-Kuster-Hauser(MRKH)syndrome.Because MRKH syndrome is a rare situation,typically sporadic cases are reported.The management of MRKH syndrome majors in the improvement of patients'sexual life,with few chances to perform laparoscopic surgery to examine the state of fallopian tubes.Lacking of series reports of the observations in fallopian tubes in MRKH syndrome patents,and no pathology evidence been reported,it is doubtful to assume that MRKH syndrome is caused by malformation of mullerian duct.Materials and MethodsData were selected from the medical record system in Peking Union Medical College Hospital.During Jan.1982 to Dec.2017,patients diagnosed as MRKH syndrome or congenital defects of uterus and vagina were admitted.The total of 113 patients were selected to meet the diagnosis and have been performed a laparoscopic operation.General information of the patients,observations during the operation and the combined gynecologic diseases or other abnormalities were reviewed,A total of 8 fallopian tubes specimens of type I MRKH syndrome and 1 normal specimens from the gynecology department of Peking Union Medical College Hospital were well preserved in-80 ?.The pathological section of was analyzed by paraffin embedding,sectioning and staining.ResultsAmong 113 patients with MRKH syndrome who underwent laparoscopic surgery in Peking Union Medical College Hospital,13 cases were found to have fallopian tube malformations,accounting for 11.5%of all patients.Malformations of the fallopian tube are often associated with renal malformations,accounting for 46%,while renal malformations account for only 13%of all patients with MRKH syndrome.Indicating that most patients have normal fallopian tubes development.The fallopian tube specimens of 8 patients with type I MRKH syndrome were examined by paraffin section and H&E staining and compared with normal tubal specimens.Preliminary results suggest that the mucosa of the oviduct and parachute is well developed in patients with MRKH syndrome,and not significantly different from normal fallopian tubes.It is confirmed that patients with MRKH syndrome do have relatively normal oviduct and parachute mucosa.Among 113 patients with MRKH syndrome who underwent laparoscopic surgery in Peking Union Medical College Hospital,13 cases were found to have fallopian tube malformations,accounting for 11.5%of all patients.Indicating that most patients have normal fallopian tubes development.Malformations of the fallopian tube are often associated with renal malformations,accounting for 46%,while renal malformations account for only 13%of all patients with MRKH syndrome,which shows statistical difference.The fallopian tube specimens of 8 patients with type I MRKH syndrome were examined by paraffin section and H&E staining and compared with normal tubal specimens.Preliminary results suggest that the mucosa of the oviduct and parachute is well developed in patients with MRKH syndrome,and not significantly different from normal fallopian tubes.It is confirmed that patients with MRKH syndrome do have relatively normal oviduct and parachute mucosa.ConclusionThe former animal gene knockout models lack the organs developed from the mullerian duct(uterus and fallopian tube),yet most of the patients(88.5%)have normal oviduct,according to the laparoscopic surgical records of the MRKH syndrome and the fallopian tube pathological analysis in our hospital.Therefore,the situations of animal models with mullerian duct development related genes knockout are not consistent with clinical observation.This prospective study of the etiology of MRKH syndrome suggests that genetic issues may not be the main factor of the cause of MRKH syndrome.BackgroundThe female genital tract originates from the mullerian duct during the embryonic period.The organs developed by mullerian duct in MRKH syndrome have malformations to different degrees.Therefore,it is generally believed that MRKH syndrome is caused by mullerian duct dysplasia.A lot of research has focused on screening potential pathogenic factors that control the development/apoptosis of mullerian duct.It has been found that Pax2 gene,Lhxl gene and Wnt4 gene play an important role in the development of mullerian duct.But the gene knockout animal models,such as Wnt-4,Pax-2,lhx-1 and other homozygous mutant embryos,can not survive postnatally,and the organs of the mullerian duct,the oviduct,uterus and vagina are all absent,which conflicts with the clinical observation.Ras signaling pathway also plays an important role in biological development,especially vaginal development of Caenorhabditis elegans.Therefore,the Ras signaling pathway may play an important role in the development of human reproductive tract and probably participate in the pathogenesis of MRKH syndrome.Materials and MethodsThe mullerian duct of female mice was cultured ex vivo,and the effects of Ras inhibitor on the development of mullerian duct in female mice were observed.The developmental of mullerian duct was confirmed by light microscopy,parafin section and staining.ResultsMiillerian duct of female mice can be differentiated and developed ex vivo,forming the structure of uterus and oviduct.Ras signaling pathway inhibitors can inhibit the development of murine mullerian duct.According to the development level of the mullerian duct,the effect of Ras signal inhibitors is different(Causing severe defect in in early stage of embryo development,while in late stage mullerian duct can form normal uterus and fallopian tube structure).The mullerian duct of E15.5d female mice can develop into a model similar to the symptoms of MRKH syndrome after adding Ras inhibitors.ConclusionRas signaling pathway is involved in the development of female reproductive tract and may be a factor contributing to pathogenesis of MRKH syndrome.